Updated on 2026/03/05

写真a

 
KUME SHOEN
 
Organization
School of Life Science and Technology Professor
Title
Professor
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News & Topics

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Degree

  • 博士（理学） ( 大阪大学 )

  • 修士 ( 東京大学 )

Research Interests

  • 発生生物学

Research Areas

  • Life Science / Developmental biology

Research History

  • Tokyo Institute of Technology   School of Life Science and Technology

    2014

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  • Kumamoto University   Institute of Molecular Embryology and Genetics   Professor

    2009 - 2014

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  • Kumamoto University Institute of Molecular Embryology and Genetics, Institute of Molecular Embriology and Genetic   Professor

    2002 - 2009

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Professional Memberships

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Papers

  • Offspring metabolic programming via the maternal diet increases susceptibility to metabolic dysregulation. International journal

    Xuguang Li, Nobuaki Shiraki, Takami Watanabe, Rikako Fukui, Kyohei Furukawa, Yusuke Kato, Yuri Nakahara, Shoen Kume, Akashi Taguchi, Youichiro Wada, Dwina Juliana Warman, Kenji Saito, Haruyo Nakajima-Adachi, Satoshi Hachimura, Hisanori Kato, Huijuan Jia

    EBioMedicine   118   105817 - 105817   2025.6

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    Language：English   Publishing type：Research paper (scientific journal)  

    BACKGROUND: Maternal nutrition during critical developmental windows is crucial for offspring metabolic programming. Methionine, an essential amino acid, is crucial in pancreatic differentiation. However, the impact of a maternal methionine-deficiency (MD) diet on offspring during the critical stage of embryonic pancreatic differentiation remains unclear. METHODS: We used an in vitro human induced pluripotent stem cell (hiPSC) differentiation model and in vivo mouse and rat models to assess the impact of short-term maternal MD during pancreatic development. Offspring metabolic outcomes were evaluated under control or high-fat diet conditions. Multi-omics analyses were performed to explore mechanistic pathways, and Ruminococcus flavefaciens supplementation was used to assess microbiota-metabolite-host interactions. FINDINGS: During foetal pancreatic development in mice, a two-day maternal MD diet induced long-term metabolic perturbations in offspring. MD disrupted pancreatic progenitor differentiation in vitro and altered offspring glucose homeostasis, pancreatic function, and gut microbiota composition in vivo. Male offspring showed impaired glucose tolerance, enhanced pancreatic differentiation, and increased susceptibility to diet-induced obesity in adulthood. These metabolic impairments were evident early in life, with MD neonates displaying altered metabolic profiles and pancreatic gene expression. We identified an association between maternal MD diet, gut microbiota-dependent R. flavefaciens abundance, and elevated creatine levels in both mothers and offspring. R. flavefaciens supplementation in mice recapitulates the observed metabolic dysregulation. INTERPRETATION: Short-term maternal MD during foetal pancreatic development can induce lasting metabolic reprogramming in offspring. Gut microbiota-dependent creatine dysregulation may serve as a key mediator linking maternal diet to offspring metabolic susceptibility. These findings highlight the developmental impact of transient maternal nutrient imbalance and role of the microbiota-metabolite axis in shaping offspring health. FUNDING: See Acknowledgements.

    DOI： 10.1016/j.ebiom.2025.105817

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  • Dynamic changes of intracellular signals in ATTR Tyr114Cys amyloidosis. International journal

    Kenta Ouchi, Takeshi Masuda, Kou Yonemaru, Kaori Isono, Yuki Ohya, Nobuaki Shiraki, Masayoshi Tasaki, Yukihiro Inomata, Mitsuharu Ueda, Takumi Era, Shoen Kume, Yukio Ando, Hirofumi Jono

    Biochemistry and biophysics reports   42   102012 - 102012   2025.6

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    Language：English   Publishing type：Research paper (scientific journal)  

    Hereditary transthyretin (TTR) amyloidosis (ATTRv amyloidosis) is an autosomal dominant disease caused by various TTR mutations. Despite the fact that ATTR Tyr114Cys (p.Tyr134Cys) amyloidosis (tyrosine to cysteine at codon 114) exhibits poorer prognosis than other ATTRv amyloidosis and leads to death due to severe clinical symptoms, the molecular pathogenesis of ATTR Tyr114Cys amyloidosis is still largely unknown. In this study, we took advantage of ATTR Tyr114Cys amyloidosis-specific induced pluripotent stem (iPS) cells to differentiate into hepatocyte-like cells (Y114C-HLCs), which are mainly TTR producing cells, and elucidated their pathogenesis. We performed proteomic analysis to comprehensively identify specific intracellular signaling pathways involved in Y114C-HLCs, and identified the specific proteins changed only in Y114C-HLCs, in comparison with disease control HLCs from ATTR Val30Met amyloidosis (V30M-HLCs). Moreover, we have succeeded in identifying several specific intracellular signals that are significantly activated in Y114C-HLCs, including cellular responses to stress and extracellular matrix organization. Our proteomic analysis is the first to report that the specific point mutations in ATTRv amyloidosis cause dynamic changes in cellular response, and reveal the specific intracellular signals may be involved in the specific pathogenesis of ATTR Tyr114Cys amyloidosis.

    DOI： 10.1016/j.bbrep.2025.102012

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  • Human pluripotent stem cell-derived intestinal organoids for pharmacokinetic studies. International journal

    Takumi Saito, Junichiro Amako, Teruhiko Watanabe, Nobuaki Shiraki, Shoen Kume

    European journal of cell biology   104 ( 2 )   151489 - 151489   2025.6

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    Language：English   Publishing type：Research paper (scientific journal)  

    The human small intestine is essential for orally administered drugs' absorption, metabolism, and excretion. Human induced pluripotent stem cell (hiPSC)-derived intestinal epithelial cells (IECs) offer a useful model for evaluating drug candidate compounds. We previously reported a protocol to generate matured enterocyte-like cells that exhibit P-gp-mediated efflux and cytochrome P450 3A (CYP3A)-mediated metabolism from human iPSCs. However, under the current protocols, generating iPSC-derived intestinal enterocyte-like cells requires a multi-step differentiation procedure and is time-consuming. Recent progress in intestinal organoid (IO) study provides an understanding of the growth factors that enable the maintenance of adult stem cells. Here, we established an easily accessible protocol using a direct 3D cluster culture to derive IOs from hiPSCs (iPSC-IOs) with high self-proliferative ability. The hiPSC-IOs can be propagated for a long-term and maintained capacity to differentiate and can be cryopreserved. Upon seeding on a two-dimensional monolayer, hiPSC-IOs gave rise to the intestinal epithelial cells (IECs) containing mature cell types of the intestine. The hiPSC-IOs-derived IECs contain enterocytes that show CYP metabolizing enzyme and transporter activities and can be used for pharmacokinetic studies.

    DOI： 10.1016/j.ejcb.2025.151489

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  • A small molecule K-3 promotes PDX1 expression and potentiates the differentiation of pluripotent stem cells into insulin-producing pancreatic β cells. International journal

    Tatsuya Yano, Yukihiro Shimaya, Takayuki Enomoto, Toshihiro Kiho, Satoshi Komoriya, Ryutaro Nakashima, Nobuaki Shiraki, Shoen Kume

    Stem cells (Dayton, Ohio)   43 ( 2 )   2025.2

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    Insulin-producing pancreatic β-like cells derived from human pluripotent stem cells (PSCs) are anticipated as a novel cell source for cell replacement therapy for patients with diabetes. Here, we describe the identification of small molecule compounds that promote the differentiation of the PSCs into insulin-producing cells by high throughput screening with a chemical library composed of 55 000 compounds. The initial hit compound K-1 and one derivative K-3 increased the proportion of PSC-derived insulin-positive endocrine cells and their glucose-stimulated insulin secretory (GSIS) functions. K-3 preferentially acts on stage 3 pancreatic progenitor cells and increases the population expressing high levels of PDX1. As a result, the ratios of the PSC-derived PDX1/NKX6.1 double-positive endocrine progenitor and INS/NKX6.1 double-positive mono-hormonal endocrine cells were increased. K-3 enhances the expression of functional pancreatic β cell markers and affects biological processes concerning organ development. K-3 also increased the yield of endocrine cells at the end of stage 5. The novel compound is a beneficial new tool for efficiently generating PSC-derived insulin-producing cells with high functionality and differentiation efficiency.

    DOI： 10.1093/stmcls/sxae075

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  • Gut-liver microphysiological systems revealed potential crosstalk mechanism modulating drug metabolism

    Dhimas Agung Kurniawan, Sylvia Leo, Mutsumi Inamatsu, Sohei Funaoka, Taichi Aihara, Mizuno Aiko, Inoue Rei, Takeshi Sakura, Hiroshi Arakawa, Yukio Kato, Tomoaki Matsugi, Katsuhiro Esashika, Nobuaki Shiraki, Shoen Kume, Kenta Shinha, Hiroshi Kimura, Masaki Nishikawa, Yasuyuki Sakai

    PNAS Nexus   2024.2

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    Publishing type：Research paper (scientific journal)   Publisher：Oxford University Press (OUP)  

    Abstract

    The small intestine and liver play important role in determining oral drug’s fate. Both organs are also interconnected through enterohepatic circulation, which imply there are crosstalk through circulating factors such as signaling molecules or metabolites that may affect drug metabolism. Coculture of hepatocytes and intestinal cells have shown to increase hepatic drug metabolism, yet its crosstalk mechanism is still unclear. In this study we aim to elucidate such crosstalk by coculturing primary human hepatocytes harvested from chimeric mouse (PXB-cells) and iPSc-derived intestinal cells in a microphysiological systems (MPS). Perfusion and direct oxygenation from the MPS were chosen and confirmed to be suitable features that enhanced PXB-cells albumin secretion, Cytochrome P450 (CYP) enzymes activity while also maintaining barrier integrity of iPSc-derived intestine cells. Results from RNA-sequencing showed significant upregulation in gene ontology terms related to fatty acids metabolism in PXB-cells. One of such fatty acids, arachidonic acid (ARA), enhanced several CYP enzyme activity in similar manner as coculture. From the current evidences, it is speculated that the release of bile acids from PXB-cells acted as stimuli for iPSc-derived intestine cells to release lipoprotein which was ultimately taken by PXB-cells and enhanced CYP activity.

    DOI： 10.1093/pnasnexus/pgae070

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  • Characterization of heterozygous ATTR Tyr114Cys amyloidosis-specific induced pluripotent stem cells. International journal

    Kenta Ouchi, Kaori Isono, Yuki Ohya, Nobuaki Shiraki, Masayoshi Tasaki, Yukihiro Inomata, Mitsuharu Ueda, Takumi Era, Shoen Kume, Yukio Ando, Hirofumi Jono

    Heliyon   10 ( 2 )   e24590   2024.1

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    Language：English   Publishing type：Research paper (scientific journal)  

    Hereditary transthyretin (TTR) amyloidosis (ATTRv amyloidosis) is autosomal dominant and caused by mutation of TTR gene. Heterozygous ATTR Tyr114Cys (p.Tyr134Cys) amyloidosis is a lethal disease with a life expectancy of about 10 years after onset of the disease. However, the molecular pathogenesis of ATTR Tyr114Cys amyloidosis is still largely unknown. In this study, we took advantage of disease-specific induced pluripotent stem (iPS) cells and generated & characterized the heterozygous ATTR Tyr114Cys amyloidosis-specific iPS cells (Y114C iPS cells), to determine whether Y114C iPS cells could be useful for elucidating the pathogenesis of ATTR Tyr114Cys amyloidosis. We successfully differentiated heterozygous Y114C iPS cells into hepatocyte like cells (HLCs) mainly producing TTR protein. On day 27 after differentiation, the expression of hepatocyte maker albumin was detected, and TTR expression was significantly increased in HLCs differentiated from Y114C iPS cells. LC-MS/MS analysis showed that both WT TTR & ATTR Y114C protein were indeed expressed in the HLCs differentiated from Y114C iPS cells. Notably, the number of detected peptides derived from ATTR Y114C protein was lower than that of WT TTR protein, indeed indicating the clinical phenotype of ATTR Tyr114Cys amyloidosis. Taken together, we first reported the heterozygous Y114C iPS cells generated from patient with ATTR Tyr114Cys amyloidosis, and suggested that Y114C iPS cells could be a potential pathological tool, which may contribute to elucidating the molecular pathogenesis of heterozygous ATTR Tyr114Cys amyloidosis.

    DOI： 10.1016/j.heliyon.2024.e24590

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  • Reversal of Hyperglycemia by Subcutaneous Islet Engraftment Using an Atelocollagen Sponge as a Scaffold. International journal

    Yumeng Wu, Tatsuya Yano, Takayuki Enomoto, Atena Endo, Seiji Okada, Kimi Araki, Nobuaki Shiraki, Shoen Kume

    Cell transplantation   33   9636897241277980 - 9636897241277980   2024

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    Type 1 diabetes mellitus (T1DM) affects 8.4 million people worldwide, with patients primarily relying on exogenous insulin injections to maintain blood glucose levels. Islet transplantation via the portal vein has allowed for the direct internal release of insulin by glucose-sensitive islets. However, this method might not be desirable for future cell therapy transplanting pluripotent stem cell-derived β cells, facing challenges including difficulties in cell retrieval and graft loss due to the instant blood-mediated inflammatory reaction (IBMIR). Here, we established a subcutaneous transplantation protocol using an atelocollagen sponge as a scaffold. While the subcutaneous site has many advantages, the lack of a vascular bed limits its application. To address this issue, we performed angiogenesis stimulation at the transplantation site using bFGF absorbed in a gelatin sponge (Spongel), significantly improving the microvascular area. Our in vivo experiments also revealed angiogenesis stimulation is crucial for reversing hyperglycemia in streptozotocin (STZ)-induced diabetic mice. In addition to the angiogenic treatment, an atelocollagen sponge is used to carry the islets and helps avoid graft leakage. With 800 mouse islets delivered by the atelocollagen sponge, the STZ-induced diabetic mice showed a reversal of hyperglycemia and normalized glucose intolerance. Their normoglycemia was maintained until the graft was removed. Analysis of the harvested islet grafts exhibited a high vascularization and preserved morphologies, suggesting that using an atelocollagen sponge as a scaffold helps maintain the viability of the islet grafts.

    DOI： 10.1177/09636897241277980

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  • A specific plasma amino acid profile in the Insulin2 Q104del Kuma mice at the diabetic state and reversal from hyperglycemia

    Naoya Hiyoshi, Takayuki Enomoto, Fumiya Uefune, Yusuke Kato, Yumeng Wu, Kimi Araki, Daisuke Sakano, Nobuaki Shiraki, Shoen Kume

    Biochemical and Biophysical Research Communications   679   58 - 65   2023.10

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    Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

    DOI： 10.1016/j.bbrc.2023.08.064

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  • Activation of cAMP (EPAC2) signaling pathway promotes hepatocyte attachment

    Grace Aprilia Helena, Teruhiko Watanabe, Yusuke Kato, Nobuaki Shiraki, Shoen Kume

    Scientific Reports   13 ( 1 )   2023.7

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    Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

    Abstract

    Primary Human Hepatocyte (PHH) remains undefeated as the gold standard in hepatic studies. Despite its valuable properties, partial attachment loss due to the extraction process and cryopreservation remained the main hurdle in its application. We hypothesized that we could overcome the loss of PHH cell attachment through thawing protocol adjustment and medium composition. We reported a novel use of a medium designed for iPSC-derived hepatocytes, increasing PHH attachment on the collagen matrix. Delving further into the medium composition, we discovered that removing BSA and exposure to cAMP activators such as IBMX and Forskolin benefit PHH attachment. We found that activating EPAC2, the cAMP downstream effector, by S-220 significantly increased PHH attachment. We also found that EPAC2 activation induced bile canaliculi formation in iPS-derived hepatocytes. Combining these factors in studies involving PHH or iPS-hepatocyte culture provides promising means to improve cell attachment and maintenance of hepatic function.

    DOI： 10.1038/s41598-023-39712-3

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    Other Link： https://www.nature.com/articles/s41598-023-39712-3

  • Selective proteasome degradation of C-terminally-truncated human WFS1 in pancreatic beta cells. International journal

    Hiraku Tokuma, Daisuke Sakano, Katsuya Tanabe, Yukio Tanizawa, Nobuaki Shiraki, Shoen Kume

    FEBS open bio   13 ( 8 )   1405 - 1414   2023.7

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    Wolfram Syndrome is a monogenic disease mainly caused by mutations in the WFS1 gene. Mutations in the WFS1 gene give rise to diabetes. Here, we characterized mutant WFS1 proteins by studying the stability of full-length wild-type WFS1, a missense mutant P724L, and two C-terminally truncated mutants, W837X and Y652X. We compared their stability by overexpressing them in MIN6 and HEK293T cells. The C-terminally truncated mutants W837X and Y652X are degraded more rapidly than the missense P724L mutant or wild-type WFS1 in MIN6 cells. In contrast, Y652X is more stable than WT or other mutant WFS1 proteins in HEK293T. In conclusion, we found that C-terminally truncated WFS1 mutants are selectively degraded in a cell type-specific manner.

    DOI： 10.1002/2211-5463.13674

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  • Protocol to generate human pluripotent stem cell-derived pancreatic β cells through methionine and zinc deprivation

    Erinn Zixuan Sim, Takayuki Enomoto, Nobuaki Shiraki, Shoen Kume

    STAR Protocols   4 ( 2 )   102183 - 102183   2023.6

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    Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

    DOI： 10.1016/j.xpro.2023.102183

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  • The effect of Vitamin D3 and Valproic Acid on the maturation of human induced pluripotent stem cell-derived enterocyte-like cells. International journal

    Sylvia Leo, Yusuke Kato, Yu Meng Wu, Mutsumi Yokota, Masato Koike, Shiro Yui, Kiichiro Tsuchiya, Nobuaki Shiraki, Shoen Kume

    Stem cells (Dayton, Ohio)   2023.5

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    Cytochrome P450 3A4 (CYP3A4) is involved in first-pass metabolism in the small intestine and is heavily implicated in oral drug bioavailability and pharmacokinetics. We previously reported that Vitamin D3 (VD3), a known CYP enzyme inducer, induces functional maturation of iPSC-derived enterocyte-like cells (iPSC-ent). Here, we identified a Notch activator and CYP modulator Valproic Acid (VPA), as a promotor for the maturation of iPSC-ent. We performed bulk RNA sequencing to investigate the changes in gene expression during the differentiation and maturation periods of these cells. VPA potentiated gene expression of key enterocyte markers ALPI, FABP2, and transporters such as SULT1B1. RNA sequencing analysis further elucidated several function-related pathways involved in fatty acid metabolism, significantly upregulated by VPA when combined with VD3. Particularly, VPA treatment in tandem with VD3 significantly upregulated key regulators of enterohepatic circulation, such as FGF19, apical bile acid transporter SLCO1A2 and basolateral bile acid transporters SLC51A and SLC51B. To sum up, we could ascertain the genetic profile of our iPSC-ent cells to be specialized towards fatty acid absorption and metabolism instead of transporting other nutrients, such as amino acids, with the addition of VD3 and VPA in tandem. Together, these results suggest the possible application of VPA-treated iPSC-ent for modelling enterohepatic circulation.

    DOI： 10.1093/stmcls/sxad042

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  • Transient Methionine Deprivation Triggers Histone Modification and Potentiates Differentiation of Induced Pluripotent Stem Cells

    Hiroki Ozawa, Azusa Kambe, Kodai Hibi, Satoshi Murakami, Akira Oikawa, Tetsuya Handa, Katsunori Fujiki, Ryuichiro Nakato, Katsuhiko Shirahige, Hiroshi Kimura, Nobuaki Shiraki, Shoen Kume

    Stem Cells   2023.3

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    Publishing type：Research paper (scientific journal)  

    DOI： 10.1093/stmcls/sxac082

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  • Generation of induced pluripotent stem cell-derived beta-cells in blood amino acids-like medium

    Marwa Ali, Yusuke Kato, Nobuaki Shiraki, Shoen Kume

    Biology Open   12 ( 3 )   2023.3

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    Publishing type：Research paper (scientific journal)   Publisher：The Company of Biologists  

    ABSTRACT

    Traditional cell culture media do not accurately represent the availability of the nutrients in plasma. They usually contain a supraphysiological concentration of nutrients such as glucose, amino acids, etc. These high nutrients can alter the metabolism of cultured cells and induce metabolic phenotypes that do not reflect in vivo conditions. We demonstrate that the supraphysiological levels of nutrients interfere with endodermal differentiation. Refinement of media formulations has a potential application in maturity modulation of stem cell-derived β-cells (SC-β) generation in vitro. To address these issues, we established a defined culture system to derive SC-β-cells using a blood amino acids-like medium (BALM). Human induced pluripotent stem cells (hiPSCs) can be efficiently differentiated into the definitive endoderm, pancreatic progenitors, endocrine progenitors, and SC-β in BALM-based med. The differentiated cells secreted C-peptide in vitro in response to high glucose levels and expressed several pancreatic β-cell markers. In conclusion, amino acids at the physiological levels are sufficient for deriving functional SC-β cells.

    DOI： 10.1242/bio.059581

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    Other Link： https://journals.logists.com/bio/bio/article-pdf/doi/10.1242/bio.059581/2647580/bio059581.pdf

  • Dopamine Negatively Regulates Insulin Secretion Through Activation of D1-D2 Receptor Heteromer

    Fumiya Uefune, Toru Aonishi, Tetsuya Kitaguchi, Harumi Takahashi, Susumu Seino, Daisuke Sakano, Shoen Kume

    DIABETES   71 ( 9 )   1946 - 1961   2022.9

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    DOI： 10.2337/db21-0644

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  • Methionine metabolism regulates pluripotent stem cell pluripotency and differentiation through zinc mobilization. International journal

    Erinn Zixuan Sim, Takayuki Enomoto, Nobuaki Shiraki, Nao Furuta, Soshiro Kashio, Taiho Kambe, Tomonori Tsuyama, Akihiro Arakawa, Hiroki Ozawa, Mizuho Yokoyama, Masayuki Miura, Shoen Kume

    Cell reports   40 ( 3 )   111120 - 111120   2022.7

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    Pluripotent stem cells (PSCs) exhibit a unique feature that requires S-adenosylmethionine (SAM) for the maintenance of their pluripotency. Methionine deprivation in the medium causes a reduction in intracellular SAM, thus rendering PSCs in a state potentiated for differentiation. In this study, we find that methionine deprivation triggers a reduction in intracellular protein-bound Zn content and upregulation of Zn exporter SLC30A1 in PSCs. Culturing PSCs in Zn-deprived medium results in decreased intracellular protein-bound Zn content, reduced cell growth, and potentiated differentiation, which partially mimics methionine deprivation. PSCs cultured under Zn deprivation exhibit an altered methionine metabolism-related metabolite profile. We conclude that methionine deprivation potentiates differentiation partly by lowering cellular Zn content. We establish a protocol to generate functional pancreatic β cells by applying methionine and Zn deprivation. Our results reveal a link between Zn signaling and methionine metabolism in the regulation of cell fate in PSCs.

    DOI： 10.1016/j.celrep.2022.111120

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  • Carborane as an Alternative Efficient Hydrophobic Tag for Protein Degradation

    Yasunobu Asawa, Kei Nishida, Kazuki Kawai, Kiyotaka Domae, Hyun Seung Ban, Akihiro Kitazaki, Hiroya Asami, Jun-Ya Kohno, Satoshi Okada, Hiraku Tokuma, Daisuke Sakano, Shoen Kume, Masaru Tanaka, Hiroyuki Nakamura

    Bioconjugate Chemistry   2021.10

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    Publishing type：Research paper (scientific journal)   Publisher：American Chemical Society (ACS)  

    DOI： 10.1021/acs.bioconjchem.1c00431

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  • Coculture with hiPS-derived intestinal cells enhanced human hepatocyte functions in a pneumatic-pressure-driven two-organ microphysiological system. International journal

    Marie Shinohara, Hiroshi Arakawa, Yuuichi Oda, Nobuaki Shiraki, Shinji Sugiura, Takumi Nishiuchi, Taku Satoh, Keita Iino, Sylvia Leo, Yusuke Kato, Karin Araya, Takumi Kawanishi, Tomoki Nakatsuji, Manami Mitsuta, Kosuke Inamura, Tomomi Goto, Kenta Shinha, Wataru Nihei, Kikuo Komori, Masaki Nishikawa, Shoen Kume, Yukio Kato, Toshiyuki Kanamori, Yasuyuki Sakai, Hiroshi Kimura

    Scientific reports   11 ( 1 )   5437 - 5437   2021.3

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    Examining intestine-liver interactions is important for achieving the desired physiological drug absorption and metabolism response in in vitro drug tests. Multi-organ microphysiological systems (MPSs) constitute promising tools for evaluating inter-organ interactions in vitro. For coculture on MPSs, normal cells are challenging to use because they require complex maintenance and careful handling. Herein, we demonstrated the potential of coculturing normal cells on MPSs in the evaluation of intestine-liver interactions. To this end, we cocultured human-induced pluripotent stem cell-derived intestinal cells and fresh human hepatocytes which were isolated from PXB mice with medium circulation in a pneumatic-pressure-driven MPS with pipette-friendly liquid-handling options. The cytochrome activity, albumin production, and liver-specific gene expressions in human hepatocytes freshly isolated from a PXB mouse were significantly upregulated via coculture with hiPS-intestinal cells. Our normal cell coculture shows the effects of the interactions between the intestine and liver that may occur in vivo. This study is the first to demonstrate the coculturing of hiPS-intestinal cells and fresh human hepatocytes on an MPS for examining pure inter-organ interactions. Normal-cell coculture using the multi-organ MPS could be pursued to explore unknown physiological mechanisms of inter-organ interactions in vitro and investigate the physiological response of new drugs.

    DOI： 10.1038/s41598-021-84861-y

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  • Generation of Human-Induced Pluripotent Stem Cell-Derived Functional Enterocyte-Like Cells for Pharmacokinetic Studies. International journal

    Shinpei Yoshida, Takayuki Honjo, Keita Iino, Ryunosuke Ishibe, Sylvia Leo, Tomoka Shimada, Teruhiko Watanabe, Masaya Ishikawa, Kazuya Maeda, Hiroyuki Kusuhara, Nobuaki Shiraki, Shoen Kume

    Stem cell reports   16 ( 2 )   295 - 308   2021.2

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    We aimed to establish an in vitro differentiation procedure to generate matured small intestinal cells mimicking human small intestine from human-induced pluripotent stem cells (iPSCs). We previously reported the efficient generation of CDX2-expressing intestinal progenitor cells from embryonic stem cells (ESCs) using 6-bromoindirubin-3'-oxime (BIO) and (3,5-difluorophenylacetyl)-L-alanyl-L-2-phenylglycine tert-butyl ester (DAPT) to treat definitive endodermal cells. Here, we demonstrate the generation of enterocyte-like cells by culturing human iPSC-derived intestinal progenitor cells on a collagen vitrigel membrane (CVM) and treating cells with a simple maturation medium containing BIO, DMSO, dexamethasone, and activated vitamin D3. Functional tests further confirmed that these iPSC-derived enterocyte-like cells exhibit P-gp- and BCRP-mediated efflux and cytochrome P450 3A4 (CYP3A4)-mediated metabolism. We concluded that hiPS cell-derived enterocyte-like cells can be used as a model for the evaluation of drug transport and metabolism studies in the human small intestine.

    DOI： 10.1016/j.stemcr.2020.12.017

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  • Recent progress in pancreatic islet cell therapy. International journal

    Erinn Zixuan Sim, Nobuaki Shiraki, Shoen Kume

    Inflammation and regeneration   41 ( 1 )   1 - 1   2021.1

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    Human pluripotent stem cells (PSCs), including human embryonic stem cells and induced pluripotent stem cells, are promising cell sources in regenerating pancreatic islets through in vitro directed differentiation. Recent progress in this research field has made it possible to generate glucose-responsive pancreatic islet cells from PSCs. Single-cell RNA sequencing techniques have been applied to analyze PSC-derived endocrine beta-cells, which are then compared with human islets. This has led to the identification of novel signaling pathways and molecules involved in lineage commitment during pancreatic differentiation and maturation processes. Single-cell transcriptomics are also used to construct a detailed map of in vivo endocrine differentiation of developing mouse embryos to study pancreatic islet development. Mimicking those occurring in vivo, it was reported that differentiating PSCs can generate similar islet cell structures, while metabolomics analysis highlighted key components involved in PSC-derived pancreatic islet cell function, providing information for the improvement of in vitro pancreatic maturation procedures. In addition, cell transplantation into diabetic animal models, together with the cell delivery system, is studied to ensure the therapeutic potentials of PSC-derived pancreatic islet cells. Combined with gene-editing technology, the engineered mutation-corrected PSC lines originated from diabetes patients could be differentiated into functional pancreatic islet cells, suggesting possible autologous cell therapy in the future. These PSC-derived pancreatic islet cells are a potential tool for studies of disease modeling and drug testing. Herein, we outlined the directed differentiation procedures of PSC-derived pancreatic islet cells, novel findings through transcriptome and metabolome studies, and recent progress in disease modeling.

    DOI： 10.1186/s41232-020-00152-5

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  • Generation of intestinal organoids derived from human pluripotent stem cells for drug testing Reviewed

    Shinpei Yoshida, Hiroto Miwa, Tomoyuki Kawachi, Shoen Kume, Koji Takahashi

    Scientific Reports   10 ( 1 )   2020.12

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    Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

    DOI： 10.1038/s41598-020-63151-z

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    Other Link： http://www.nature.com/articles/s41598-020-63151-z

  • VMAT2 Safeguards β-Cells Against Dopamine Cytotoxicity Under High-Fat Diet–Induced Stress

    Daisuke Sakano, Fumiya Uefune, Hiraku Tokuma, Yuki Sonoda, Kumi Matsuura, Naoki Takeda, Naomi Nakagata, Kazuhiko Kume, Nobuaki Shiraki, Shoen Kume

    Diabetes   69 ( 11 )   2377 - 2391   2020.11

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    Publishing type：Research paper (scientific journal)   Publisher：American Diabetes Association  

    DOI： 10.2337/db20-0207

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    Other Link： https://syndication.highwire.org/content/doi/10.2337/db20-0207

  • Insulin2Q104del (Kuma) mutant mice develop diabetes with dominant inheritance. Reviewed International journal

    Daisuke Sakano, Airi Inoue, Takayuki Enomoto, Mai Imasaka, Seiji Okada, Mutsumi Yokota, Masato Koike, Kimi Araki, Shoen Kume

    Scientific reports   10 ( 1 )   12187 - 12187   2020.7

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    Insulin gene mutations have been identified to cause monogenic diabetes, and most of which developed permanent neonatal diabetes at young ages before 6 months of age in humans. To establish an animal model of permanent diabetes, we performed genome editing using the CRISPR/Cas9 system. We generated a novel Kuma mutant mice with p.Q104del in the Insulin2 (Ins2) gene in a BRJ background that exhibits a severe immune deficiency. Kuma mutant mice are non-obese and developed hyperglycemia from 3 weeks after birth in both males and females, which are inherited in a dominant mode. Kuma mutant mice displayed reduced insulin protein levels from 3-weeks-old, which seem to be caused by the low stability of the mutant insulin protein. Kuma mutant showed a reduction in islet size and islet mass. Electron microscopic analysis revealed a marked decrease in the number and size of insulin granules in the beta-cells of the mutant mice. Hyperglycemia of the mutant can be rescued by insulin administration. Our results present a novel insulin mutation that causes permanent early-onset diabetes, which provides a model useful for islet transplantation studies.

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  • Detailed analysis at a single‐cell level of cells undergoing pancreatic differentiation Reviewed

    Nobuaki Shiraki, Shoen Kume

    Journal of Diabetes Investigation   11 ( 1 )   20 - 21   2020.1

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    Pancreatic cells derived from pluripotent stem cells using the stem cell-derived-β (SC-β) differentiation protocol are composed of four main cell types, namely β-like cells (SC-β-cells), α-like cells, enterochromaffin-like cells and non-endocrine cells. Single-cell dissociation and reaggregation depleted non-endocrine cells and improved β-cell function. Veres et al. succeeded in efficiently purifying SC-β by magnetic cell sorting using CD49a antibody and reaggregation, so that the final SC-β-cell ratio increased to 80%.

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  • Collagen vitrigel promotes hepatocytic differentiation of induced pluripotent stem cells into functional hepatocyte-like cells Reviewed International journal

    Shun Nakai, Ima Shibata, Takahiro Shitamichi, Hiroyuki Yamaguchi, Nobuyuki Takagi, Tomoaki Inoue, Toshito Nakagawa, Jumpei Kiyokawa, Satoshi Wakabayashi, Tomoya Miyoshi, Eriko Higashi, Seiichi Ishida, Nobuaki Shiraki, Shoen Kume

    Biology Open   8 ( 7 )   bio042192 - bio042192   2019.7

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    Differentiation of stem cells to hepatocytes provides an unlimited supply of human hepatocytes and therefore has been vigorously studied. However, to date, the stem cell-derived hepatocytes were suggested to be of immature features. To obtain matured hepatocytes from stem cells, we tested the effect of culturing human-induced pluripotent stem (hiPS) cell-derived endoderm cells on collagen vitrigel membrane and compared with our previous reported nanofiber matrix. We cultured hiPS cell-derived endoderm cells on a collagen vitrigel membrane and examined the expression profiles, and tested the activity of metabolic enzymes. Gene expression profile analysis of hepatocytic differentiation markers revealed that upon culture on collagen vitrigel membrane, immature markers of AFP decreased, with a concomitant increase in the expression of mature hepatocyte transcription factors and mature hepatocyte markers such as ALB, ASGR1 Mature markers involved in liver functions, such as transporters, cytochrome P450 enzymes and phase II metabolic enzymes were also upregulated. We observed the upregulation of the liver markers for at least 2 weeks. Gene array profiling analysis revealed that hiPS cell-derived hepatocyte-like cells (hiPS-hep) resemble those of the primary hepatocytes. Functions of the CYP enzyme activities were tested in multi-institution and all revealed high CYP1A, CYP2C19, CYP2D6, CYP3A activity, which could be maintained for at least 2 weeks in culture. Taken together, the present approach identified that collagen vitrigel membrane provides a suitable environment for the generation of hepatocytes from hiPS cells that resemble many characteristics of primary human hepatocytes.

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  • Future Perspectives for the Treatment of Diabetes: Importance of a Regulatory Framework Reviewed International journal

    Katsura Tsukamoto, Miriam Cnop, Daichi Mori, Shoen Kume, Takayuki Anazawa, Masako Doi, Kazuhiko Chikazawa, Naoki Matsumaru

    Therapeutic Innovation & Regulatory Science   53 ( 4 )   535 - 541   2019.7

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    BACKGROUND: The number of diabetes patients is steadily increasing worldwide. Consequently, the social burden of diabetes is huge, requiring urgent countermeasures. We performed an intensive survey of antidiabetic drugs approved in Japan, the United States, and the European Union. METHODS: Information about approved antidiabetic drugs was obtained by searching databases of regulatory authorities in the 3 regions. Other relevant information was also obtained from publicly available literature and documents. RESULTS: No difference in the total number and types of approved drugs among the 3 regions was found (P = .173 by log-rank test). However, the numbers of approved dipeptidyl peptidase-4 and sodium-glucose cotransporter 2 inhibitors in Japan were almost double of those in the other regions. The average sample size in clinical trials used for antidiabetic drug approval in Japan (1134 patients) was much smaller than that in the other regions (P < .001 by analysis of variance repeated measures test adjusted by the Holm method). Currently, 6 drugs with known modes of action are being developed for type 1 diabetes in Japan, whereas at the end of 2016, nearly 7-fold more products with novel modes of action were in clinical development in the United States. CONCLUSION: Antidiabetic drug development in Japan costs less than that in the other regions, although novel development is less active because of regulatory differences. To achieve better pharmacotherapy for diabetes, the regulatory framework requires careful consideration.

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  • 網目構造の合成繊維シートから成る培養担体は多能性幹細胞の膵臓系譜への分化を促進する

    貝塚 拓, 小島 理恵, 川部 雅章, 野口 洋文, 白木 伸明, 粂 昭苑, 富澤 一仁

    組織培養研究   38 ( 2 )   123 - 123   2019.6

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  • A culture substratum with net-like polyamide fibers promotes the differentiation of mouse and human pluripotent stem cells to insulin-producing cells. Reviewed International journal

    Kaitsuka T, Kojima R, Kawabe M, Noguchi H, Shiraki N, Kume S, Tomizawa K

    Biomedical materials (Bristol, England)   14 ( 4 )   045019 - 045019   2019.6

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    Insulin-producing and -secreting cells derived from mouse pluripotent stem cells (PSCs) are useful for pancreatic development research and evaluating drugs that may induce insulin secretion. Previously, we have established a differentiation protocol to derive insulin-secreting cells from mouse embryonic stem cells (ESCs) using a combination of growth factors, recombinant proteins, and a culture substratum with net-like fibers. However, it has not been tested which materials and diameters of these fibers are more effective for the differentiation. Therefore, the present study aimed to produce net-like culture substratum formed from polyamide (PA) and polyacrylonitrile (PAN) fibers. Substrata were delineated into PA100, 300, 600, PAN100, 300, and 600 groups based on fiber diameters. The differentiation efficiencies of mouse ESCs cultured on the substrata were then examined by insulin 1 (Ins1) expression. Expression was found to be highest in PA300 differentiated cells, indicating the potential to produce high levels of insulin. To understand any differences in substratum properties, the adsorption capacities of laminin were measured, revealing that PA300 had the highest for it. We next examined the stage of differentiation affected by incubation with PA300. This showed that Sox17- and Pdx1-GFP-positive cells increased during the first step of differentiation. To show the production of insulin without absorption from the medium, we confirmed the expression of insulin C-peptide after differentiation. Finally, we tested the effects of PA300 on the differentiation of human-induced PSC, and found more Sox17-positive cells with the PA300 substratum at the definitive endoderm stage. Furthermore, these cells expressed insulin C-peptide and had glucose-responsive C-peptide secretion. In summary, our study identified and validated a novel substratum which is suitable for pancreatic differentiation of mouse and human PSCs.

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  • Induced Pluripotent Stem Cell Elimination in a Cell Sheet by Methionine-Free and 42°C Condition for Tumor Prevention. Reviewed International journal

    Matsuura K, Ito K, Shiraki N, Kume S, Hagiwara N, Shimizu T

    Tissue engineering. Part C, Methods   24 ( 10 )   605 - 615   2018.10

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    Pluripotent stem cells, including induced pluripotent stem (iPS) cells, are promising cell sources for regenerative medicine to replace injured tissues, and tissue engineering technologies enable engraftment of functional iPS cell-derived cells in vivo for prolonged periods. However, the risk of tumor formation is a concern for the use of iPS cells. Bioengineered tissues provide a suitable environment for cell survival, which requires vigorous efforts to eliminate remaining iPS cells and prevent tumor formation. We recently reported three iPS cell elimination strategies, including methionine-free medium, TRPV1 activation through 42°C cultivation, and dinaciclib, a cyclin-dependent kinase 1/9 inhibitor. However, it remains unclear how many iPS cells in bioengineered tissues can be eliminated using these strategies alone or in combination, as well as the mode of subsequent tumor prevention. In the present study, we found that 2 days of cultivation at 42°C sufficiently eliminated 1 × 102 iPS cells in fibroblast sheets and prevented tumor formation. After screening for suitable combinations of these strategies based on Lin28 expression in co-cultures of fibroblasts and 1 × 104 iPS cells, we found that 1 day of cultivation at 42°C in methionine-free culture medium with or without dinaciclib remarkably decreased Lin28 expression and prevented tumor formation. Furthermore, these culture strategies did not affect spontaneous beating or the cell number of human iPS cell-derived cardiomyocytes. These quantitative findings may contribute to decreasing tumor formation risk and development of regenerative medicine using iPS cells.

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  • Inhibition of Cdk5 promotes β-cell differentiation from ductal progenitors Reviewed

    Ka-Cheuk Liu, Gunter Leuckx, Daisuke Sakano, Philip A. Seymour, Charlotte L. Mattsson, Linn Rautio, Willem Staels, Yannick Verdonck, Palle Serup, Shoen Kume, Harry Heimberg, Olov Andersson

    Diabetes   67 ( 1 )   58 - 70   2018.1

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    DOI： 10.2337/db16-1587

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  • Different murine-derived feeder cells alter the definitive endoderm differentiation of human induced pluripotent stem cells. Reviewed

    Shoji M, Minato H, Ogaki S, Seki M, Suzuki Y, Kume S, Kuzuhara T

    PLosONE   13 ( 7 )   e0201239   2018

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  • Sweetness induces sleep through gustatory signalling independent of nutritional value in a starved fruit fly Reviewed

    Tatsuya Hasegawa, Jun Tomita, Rina Hashimoto, Taro Ueno, Shoen Kume, Kazuhiko Kume

    SCIENTIFIC REPORTS   7   2017.10

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    DOI： 10.1038/s41598-017-14608-1

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  • Erythropoietin facilitates definitive endodermal differentiation of mouse embryonic stem cells via activation of ERK signaling Reviewed

    Taku Kaitsuka, Kohei Kobayashi, Wakako Otsuka, Takuya Kubo, Farzana Hakim, Fan-Yan Wei, Nobuaki Shiraki, Shoen Kume, Kazuhito Tomizawa

    AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY   312 ( 5 )   C573 - C582   2017.5

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    DOI： 10.1152/ajpcell.00071.2016

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  • Mild electrical stimulation with heat shock guides differentiation of embryonic stem cells into Pdx1-expressing cells within the definitive endoderm Reviewed

    Tomoaki Koga, Nobuaki Shiraki, Shuichiro Yano, Mary Ann Suico, Saori Morino-Koga, Takashi Sato, Tsuyoshi Shuto, Shoen Kume, Hirofumi Kai

    BMC BIOTECHNOLOGY   17   2017.2

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    DOI： 10.1186/s12896-017-0331-z

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  • Heterogeneity of b-cells. Reviewed

    Kume S

    J Diabetes Investig. 8(5):656-657   2017

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  • Changes in expression of C2cd4c in pancreatic endocrine cells during pancreatic development Reviewed

    Hisayoshi Omori, Soichiro Ogaki, Daisuke Sakano, Mutsumi Sato, Kahoko Umeda, Naoki Takeda, Naomi Nakagata, Shoen Kume

    FEBS LETTERS   590 ( 16 )   2584 - 2593   2016.8

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    DOI： 10.1002/1873-3468.12271

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  • Dopamine D2 Receptor-Mediated Regulation of Pancreatic beta Cell Mass Reviewed

    Daisuke Sakano, Sungik Choi, Masateru Kataoka, Nobuaki Shiraki, Motonari Uesugi, Kazuhiko Kume, Shoen Kume

    STEM CELL REPORTS   7 ( 1 )   95 - 109   2016.7

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    DOI： 10.1016/j.stemcr.2016.05.015

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  • Temporal effects of Notch signaling and potential cooperation with multiple downstream effectors on adenohypophysis cell specification in zebrafish Reviewed

    Yoshinari Nakahara, Akihiko Muto, Ryo Hirabayashi, Tetsushi Sakuma, Takashi Yamamoto, Shoen Kume, Yutaka Kikuchi

    GENES TO CELLS   21 ( 5 )   492 - 504   2016.5

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    DOI： 10.1111/gtc.12358

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  • Late stage definitive endodermal differentiation can be defined by Daf1 expression Reviewed

    Soichiro Ogaki, Hisayoshi Omori, Mayu Morooka, Nobuaki Shiraki, Seiichi Ishida, Shoen Kume

    BMC DEVELOPMENTAL BIOLOGY   16   2016.5

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    DOI： 10.1186/s12861-016-0120-2

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  • Speciation of Intracellular Zn, Fe and Cu within both iPS Cells and Differentiated Cells Using HPLC Coupled to ICP-MS

    Arakawa A, Shiraki N, Tsuyama T, Kume S, Iwahata D, Yamada N

    Journal of Analytical &amp; Bioanalytical Techniques   7 ( 1 )   2016

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    DOI： 10.4172/2155-9872.1000295

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  • Definitive Endoderm Differentiation of Human Embryonic Stem Cells Combined with Selective Elimination of Undifferentiated Cells by Methionine Deprivation. Reviewed International journal

    Tomonori Tsuyama, Nobuaki Shiraki, Shoen Kume

    Methods in molecular biology (Clifton, N.J.)   1307   205 - 12   2016

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    Human embryonic stem cells (ESCs) show a characteristic feature in that they are highly dependent on methionine metabolism. Undifferentiated human ESCs cannot survive under the condition that methionine is deprived from culture medium. We describe here a procedure for definitive endoderm differentiation from human ESCs, in which human ESCs are subject to 10 days (d) differentiation combined with methionine deprivation between differentiation day (d) 8 to d10. Methionine deprivation results in elimination of undifferentiated cells from the culture with no significant loss of definitive endoderm cells, as compared to those cultured under complete condition throughout the whole culture period.

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  • Pancreatic Differentiation from Murine Embryonic Stem Cells. Reviewed International journal

    Daisuke Sakano, Nobuaki Shiraki, Shoen Kume

    Methods in molecular biology (Clifton, N.J.)   1341   417 - 23   2016

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    Pluripotent stem cells are considered as a cell source for replacement therapies for pancreatic beta cells and other organs.We identified tetrabenazine (TBZ), vesicular monoamine transporter 2 (VMAT2) inhibitor as a promoter of late-stage differentiation of Pdx1-positive pancreatic progenitor cells into Ngn3-positive endocrine progenitor cells. A cell-permeable cAMP analog, dBu-cAMP promotes beta cell maturation in late stage of differentiation. The induced beta cells can secrete insulin in a glucose-dependent manner.Our protocol consists of a three -step differentiation process. ES cell recapitulate embryonic developmental processes in vitro. Therefore, the ES cell differentiation system is a useful model for the understanding of molecular mechanism of beta-cell differentiation and are useful for application for future regenerative medicine.

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  • Neural cells play an inhibitory role in pancreatic differentiation of pluripotent stem cells Reviewed

    Ryutaro Nakashima, Mayu Morooka, Nobuaki Shiraki, Daisuke Sakano, Soichiro Ogaki, Kazuhiko Kume, Shoen Kume

    GENES TO CELLS   20 ( 12 )   1028 - 1045   2015.12

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    DOI： 10.1111/gtc.12308

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  • A cost-effective system for differentiation of intestinal epithelium from human induced pluripotent stem cells Reviewed

    Soichiro Ogaki, Mayu Morooka, Kaito Otera, Shoen Kume

    SCIENTIFIC REPORTS   5   2015.11

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    DOI： 10.1038/srep17297

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  • Endoderm differentiation of iPS cells.

    Nobuaki Shiraki, Shoen Kume

    Nihon rinsho. Japanese journal of clinical medicine   73 Suppl 5   107 - 14   2015.6

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  • The NMDA Receptor Promotes Sleep in the Fruit Fly, Drosophila melanogaster Reviewed

    Jun Tomita, Taro Ueno, Madoka Mitsuyoshi, Shoen Kume, Kazuhiko Kume

    PLOS ONE   10 ( 5 )   2015.5

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    DOI： 10.1371/journal.pone.0128101

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  • [Methionine metabolism regulates maintenance and differentiation of human ES/iPS cells]. Reviewed

    Shiraki N, Kume S, Nihon rinsho, Japanese journal of clinical medicine

    73 ( 5 )   765 - 772   2015.5

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    Shiraki N, Kume S, Nihon rinsho. Japanese journal of clinical medicine, 2015, vol. 73, no. 5, pp. 765-772

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  • Sexually dimorphic expression of Mafb regulates masculinization of the embryonic urethral formation Reviewed

    Kentaro Suzuki, Tomokazu Numata, Hiroko Suzuki, Dennis Diana Raga, Lerrie Ann Ipulan, Chikako Yokoyama, Shoko Matsushita, Michito Hamada, Naomi Nakagata, Ryuichi Nishinakamura, Shoen Kume, Satoru Takahashi, Gen Yamada

    PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA   111 ( 46 )   16407 - 16412   2014.11

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    DOI： 10.1073/pnas.1413273111

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  • Generation of insulin-producing beta-like cells from human iPS cells in a defined and completely xeno-free culture system Reviewed

    Hussain Md. Shahjalal, Nobuaki Shiraki, Daisuke Sakano, Kazuhide Kikawa, Soichiro Ogaki, Hideo Baba, Kazuhiko Kume, Shoen Kume

    JOURNAL OF MOLECULAR CELL BIOLOGY   6 ( 5 )   394 - 408   2014.10

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  • Potentiation of insulin secretion and improvement of glucose intolerance by combining a novel G protein-coupled receptor 40 agonist DS-1558 with glucagon-like peptide-1 receptor agonists Reviewed

    Ryutaro Nakashima, Tatsuya Yano, Junko Ogawa, Naomi Tanaka, Narihiro Toda, Masao Yoshida, Rieko Takano, Masahiro Inoue, Takeshi Honda, Shoen Kume, Koji Matsumoto

    EUROPEAN JOURNAL OF PHARMACOLOGY   737   194 - 201   2014.8

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  • Methionine Metabolism Regulates Maintenance and Differentiation of Human Pluripotent Stem Cells Reviewed

    Nobuaki Shiraki, Yasuko Shiraki, Tomonori Tsuyama, Fumiaki Obata, Masayuki Miura, Genta Nagae, Hiroyuki Aburatani, Kazuhiko Kume, Fumio Endo, Shoen Kume

    CELL METABOLISM   19 ( 5 )   780 - 794   2014.5

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  • Beneficial Effect of Insulin Treatment on Islet Transplantation Outcomes in Akita Mice Reviewed

    Kazuhide Kikawa, Daisuke Sakano, Nobuaki Shiraki, Tomonori Tsuyama, Kazuhiko Kume, Fumio Endo, Shoen Kume

    PLOS ONE   9 ( 4 )   2014.4

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  • High Oxygen Condition Facilitates the Differentiation of Mouse and Human Pluripotent Stem Cells into Pancreatic Progenitors and Insulin-producing Cells* Reviewed

    Farzana Hakim, Taku Kaitsuka, Jamiruddin Mohd Raeed, Fan-Yan Wei, Nobuaki Shiraki, Tadayuki Akagi, Takashi Yokota, Shoen Kume, Kazuhito Tomizawa

    JOURNAL OF BIOLOGICAL CHEMISTRY   289 ( 14 )   9623 - 9638   2014.4

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    DOI： 10.1074/jbc.M113.524363

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  • Generation of familial amyloidotic polyneuropathy-specific induced pluripotent stem cells Reviewed

    Kaori Isono, Hirofumi Jono, Yuki Ohya, Nobuaki Shiraki, Taiji Yamazoe, Ayaka Sugasaki, Takumi Era, Noemi Fusaki, Masayoshi Tasaki, Mitsuharu Ueda, Satoru Shinriki, Yukihiro Inomata, Shoen Kume, Yukio Ando

    STEM CELL RESEARCH   12 ( 2 )   574 - 583   2014.3

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  • VMAT2 identified as a regulator of late-stage β-cell differentiation. Reviewed International journal

    Daisuke Sakano, Nobuaki Shiraki, Kazuhide Kikawa, Taiji Yamazoe, Masateru Kataoka, Kahoko Umeda, Kimi Araki, Di Mao, Shirou Matsumoto, Naomi Nakagata, Olov Andersson, Didier Stainier, Fumio Endo, Kazuhiko Kume, Motonari Uesugi, Shoen Kume

    Nature chemical biology   10 ( 2 )   141 - 8   2014.2

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    Cell replacement therapy for diabetes mellitus requires cost-effective generation of high-quality, insulin-producing, pancreatic β cells from pluripotent stem cells. Development of this technique has been hampered by a lack of knowledge of the molecular mechanisms underlying β-cell differentiation. The present study identified reserpine and tetrabenazine (TBZ), both vesicular monoamine transporter 2 (VMAT2) inhibitors, as promoters of late-stage differentiation of Pdx1-positive pancreatic progenitor cells into Neurog3 (referred to henceforth as Ngn3)-positive endocrine precursors. VMAT2-controlled monoamines, such as dopamine, histamine and serotonin, negatively regulated β-cell differentiation. Reserpine or TBZ acted additively with dibutyryl adenosine 3',5'-cyclic AMP, a cell-permeable cAMP analog, to potentiate differentiation of embryonic stem (ES) cells into β cells that exhibited glucose-stimulated insulin secretion. When ES cell-derived β cells were transplanted into AKITA diabetic mice, the cells reversed hyperglycemia. Our protocol provides a basis for the understanding of β-cell differentiation and its application to a cost-effective production of functional β cells for cell therapy.

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  • Generation of Functional Insulin-Producing Cells From Mouse Embryonic Stem Cells Through 804G Cell-Derived Extracellular Matrix and Protein Transduction of Transcription Factors Reviewed

    Taku Kaitsuka, Hirofumi Noguchi, Nobuaki Shiraki, Takuya Kubo, Fan-Yan Wei, Farzana Hakim, Shoen Kume, Kazuhito Tomizawa

    STEM CELLS TRANSLATIONAL MEDICINE   3 ( 1 )   114 - 127   2014.1

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  • Profiling of embryonic stem cell differentiation Reviewed

    Nobuaki Shiraki, Soichiro Ogaki, Shoen Kume

    Review of Diabetic Studies   11 ( 1 )   102 - 114   2014

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  • A synthetic nanofibrillar matrix promotes in vitro hepatic differentiation of embryonic stem cells and induced pluripotent stem cells Reviewed

    Taiji Yamazoe, Nobuaki Shiraki, Masashi Toyoda, Nobutaka Kiyokawa, Hajime Okita, Yoshitaka Miyagawa, Hidenori Akutsu, Akihiro Umezawa, Yutaka Sasaki, Kazuhiko Kume, Shoen Kume

    JOURNAL OF CELL SCIENCE   126 ( 23 )   5391 - 5399   2013.12

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    DOI： 10.1242/jcs.129767

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  • Temporal organization of rest defined by actigraphy data in healthy and childhood chronic fatigue syndrome children Reviewed

    Minako Kawabata, Taro Ueno, Jun Tomita, Junko Kawatani, Akemi Tomoda, Shoen Kume, Kazuhiko Kume

    BMC PSYCHIATRY   13   2013.11

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    DOI： 10.1186/1471-244X-13-281

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  • Wnt and Notch Signals Guide Embryonic Stem Cell Differentiation into the Intestinal Lineages Reviewed

    Soichiro Ogaki, Nobuaki Shiraki, Kazuhiko Kume, Shoen Kume

    STEM CELLS   31 ( 6 )   1086 - 1096   2013.6

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    DOI： 10.1002/stem.1344

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  • Secreted Cerberus1 as a Marker for Quantification of Definitive Endoderm Differentiation of the Pluripotent Stem Cells Reviewed

    Hidefumi Iwashita, Nobuaki Shiraki, Daisuke Sakano, Takashi Ikegami, Masanobu Shiga, Kazuhiko Kume, Shoen Kume

    PLOS ONE   8 ( 5 )   2013.5

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  • Albumin gene targeting in human embryonic stem cells and induced pluripotent stem cells with helper-dependent adenoviral vector to monitor hepatic differentiation Reviewed

    Kahoko Umeda, Keiichiro Suzuki, Taiji Yamazoe, Nobuaki Shiraki, Yuichiro Higuchi, Kumiko Tokieda, Kazuhiko Kume, Kohnosuke Mitani, Shoen Kume

    Stem Cell Research   10 ( 2 )   179 - 194   2013.3

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  • Recovery from diabetes in neonatal mice after a low-dose streptozotocin treatment Reviewed

    Masateru Kataoka, Yuki Kawamuro, Nobuaki Shiraki, Rika Miki, Daisuke Sakano, Tetsu Yoshida, Takanori Yasukawa, Kazuhiko Kume, Shoen Kume

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS   430 ( 3 )   1103 - 1108   2013.1

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    DOI： 10.1016/j.bbrc.2012.12.030

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  • The role of CXCL12-CXCR4 signaling pathway in pancreatic development Reviewed

    Keiichi Katsumoto, Shoen Kume

    Theranostics   3 ( 1 )   11 - 17   2013

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  • Identification of a dopamine pathway that regulates sleep and arousal in Drosophila Reviewed

    Taro Ueno, Jun Tomita, Hiromu Tanimoto, Keita Endo, Kei Ito, Shoen Kume, Kazuhiko Kume

    NATURE NEUROSCIENCE   15 ( 11 )   1516 - 1523   2012.11

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    DOI： 10.1038/nn.3238

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  • Dopamine Modulates Metabolic Rate and Temperature Sensitivity in Drosophila melanogaster Reviewed

    Taro Ueno, Jun Tomita, Shoen Kume, Kazuhiko Kume

    PLOS ONE   7 ( 2 )   2012.2

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    DOI： 10.1371/journal.pone.0031513

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  • Dopamine Modulates the Rest Period Length without Perturbation of Its Power Law Distribution in Drosophila melanogaster Reviewed

    Taro Ueno, Naoki Masuda, Shoen Kume, Kazuhiko Kume

    PLOS ONE   7 ( 2 )   2012.2

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    DOI： 10.1371/journal.pone.0032007

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  • Pan-neuronal knockdown of the c-Jun N-terminal Kinase (JNK) results in a reduction in sleep and longevity in Drosophila Reviewed

    Kazuhiro Takahama, Jun Tomita, Taro Ueno, Masako Yamazaki, Shoen Kume, Kazuhiko Kume

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS   417 ( 2 )   807 - 811   2012.1

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    DOI： 10.1016/j.bbrc.2011.12.040

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  • Fate maps of ventral and dorsal pancreatic progenitor cells in early somite stage mouse embryos Reviewed

    Rika Miki, Tetsu Yoshida, Kazuya Murata, Shinya Oki, Kazuhiko Kume, Shoen Kume

    MECHANISMS OF DEVELOPMENT   128 ( 11-12 )   597 - 609   2012.1

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    DOI： 10.1016/j.mod.2011.12.004

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  • High calorie diet augments age-associated sleep impairment in Drosophila Reviewed

    Masako Yamazaki, Jun Tomita, Kazuhiro Takahama, Taro Ueno, Madoka Mitsuyoshi, Erina Sakamoto, Shoen Kume, Kazuhiko Kume

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS   417 ( 2 )   812 - 816   2012.1

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    DOI： 10.1016/j.bbrc.2011.12.041

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  • DNA Methylation Profiling of Embryonic Stem Cell Differentiation into the Three Germ Layers Reviewed

    Takayuki Isagawa, Genta Nagae, Nobuaki Shiraki, Takanori Fujita, Noriko Sato, Shumpei Ishikawa, Shoen Kume, Hiroyuki Aburatani

    PLOS ONE   6 ( 10 )   2011.10

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    DOI： 10.1371/journal.pone.0026052

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  • Pan-Neuronal Knockdown of Calcineurin Reduces Sleep in the Fruit Fly, Drosophila melanogaster Reviewed

    Jun Tomita, Madoka Mitsuyoshi, Taro Ueno, Yoshinori Aso, Hiromu Tanimoto, Yasuhiro Nakai, Toshiro Aigaki, Shoen Kume, Kazuhiko Kume

    JOURNAL OF NEUROSCIENCE   31 ( 37 )   13137 - 13146   2011.9

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    DOI： 10.1523/JNEUROSCI.5860-10.2011

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  • Influence of 60 ns pulsed electric fields on embryonic stem cells Reviewed

    Masahiro Akiyama, Eri Shiraishi, Takashi Sakugawa, S. H.R. Hosseini, Hidenori Akiyama, Nobuaki Shiraki, Shoen Kume

    IEEE Transactions on Dielectrics and Electrical Insulation   18 ( 4 )   1119 - 1123   2011.8

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    DOI： 10.1109/TDEI.2011.5976104

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  • Efficient Differentiation of Embryonic Stem Cells into Hepatic Cells In Vitro Using a Feeder-Free Basement Membrane Substratum Reviewed

    Nobuaki Shiraki, Taiji Yamazoe, Zeng Qin, Keiko Ohgomori, Katsumi Mochitate, Kazuhiko Kume, Shoen Kume

    PLOS ONE   6 ( 8 )   2011.8

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    DOI： 10.1371/journal.pone.0024228

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  • Xenopus Embryos and ES Cells as Tools for Studies of Developmental Biology Reviewed

    Shoen Kume

    NEUROCHEMICAL RESEARCH   36 ( 7 )   1280 - 1285   2011.7

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    DOI： 10.1007/s11064-010-0350-9

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  • Tissue-specific demethylation in CpG-poor promoters during cellular differentiation Reviewed

    Genta Nagae, Takayuki Isagawa, Nobuaki Shiraki, Takanori Fujita, Shogo Yamamoto, Shuichi Tsutsumi, Aya Nonaka, Sayaka Yoshiba, Keisuke Matsusaka, Yutaka Midorikawa, Shumpei Ishikawa, Hidenobu Soejima, Masashi Fukayama, Hirofumi Suemori, Norio Nakatsuji, Shoen Kume, Hiroyuki Aburatani

    HUMAN MOLECULAR GENETICS   20 ( 14 )   2710 - 2721   2011.7

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    DOI： 10.1093/hmg/ddr170

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  • Endoderm and mesoderm reciprocal signaling mediated by CXCL12 and CXCR4 regulates the migration of angioblasts and establishes the pancreatic fate Reviewed

    Keiichi Katsumoto, Shoen Kume

    DEVELOPMENT   138 ( 10 )   1947 - 1955   2011.5

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    DOI： 10.1242/dev.058719

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  • An expression profile analysis of ES cell-derived definitive endodermal cells and Pdx1-expressing cells Reviewed

    Soichiro Ogaki, Seiko Harada, Nobuaki Shiraki, Kazuhiko Kume, Shoen Kume

    BMC DEVELOPMENTAL BIOLOGY   11   2011.3

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    DOI： 10.1186/1471-213X-11-13

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  • Epiplakin1 is expressed in the cholangiocyte lineage cells in normal liver and adult progenitor cells in injured liver Reviewed

    Akira Matsuo, Tetsu Yoshida, Takanori Yasukawa, Rika Miki, Kazuhiko Kume, Shoen Kume

    GENE EXPRESSION PATTERNS   11 ( 3-4 )   255 - 262   2011.3

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    DOI： 10.1016/j.gep.2011.01.001

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  • In vitro models of pancreatic differentiation using embryonic stem or induced pluripotent stem cells Reviewed

    Yuichiro Higuchi, Nobuaki Shiraki, Shoen Kume

    CONGENITAL ANOMALIES   51 ( 1 )   21 - 25   2011.3

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  • The view of stem cell therapy for type 1 diabetes Reviewed

    Sakano D, Shiraki N, Kume S

    Journal of the Japan Diabetes Society   54 ( 4 )   268 - 270   2011

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  • エピプラキン1(Eppk1)は発生過程、成体および損傷肝における胆管細胞およびtransit amplifying細胞をマークする(Epiplakin1(Eppk1) marks the cholangiocytes and transit amplifying cells in developing, adult and injured liver)

    松尾 顕, 吉田 哲, 三木 梨可, 藤原 作平, 粂 和彦, 粂 昭苑

    日本生化学会大会・日本分子生物学会年会合同大会講演要旨集   83回・33回   2P - 0757   2010.12

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  • カルシニューリンによるショウジョウバエの睡眠および記憶の制御(Calcineurin regulates sleep and memory in Drosophila)

    冨田 淳, 光吉 まどか, 上野 太郎, 麻生 能功, 谷本 拓, 粂 昭苑, 粂 和彦

    神経化学   49 ( 2-3 )   570 - 570   2010.8

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  • ドーパミンによるショウジョウバエの代謝および温度嗜好性の制御(Dopamine controls temperature preferences and energy homeostasis in Drosophila melanogaster)

    上野 太郎, 粂 昭苑, 粂 和彦

    神経化学   49 ( 2-3 )   738 - 738   2010.8

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  • Synthesized basement membranes direct the differentiation of mouse embryonic stem cells into pancreatic lineages Reviewed

    Yuichiro Higuchi, Nobuaki Shiraki, Keitaro Yamane, Zeng Qin, Katsumi Mochitate, Kimi Araki, Takafumi Senokuchi, Kazuya Yamagata, Manami Hara, Kazuhiko Kume, Shoen Kume

    JOURNAL OF CELL SCIENCE   123 ( 16 )   2733 - 2742   2010.8

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    DOI： 10.1242/jcs.066886

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  • Embryonic and adult stem cell systems in mammals: Ontology and regulation Reviewed

    Keiichi Katsumoto, Nobuaki Shiraki, Rika Miki, Shoen Kume

    DEVELOPMENT GROWTH & DIFFERENTIATION   52 ( 1 )   115 - 129   2010.1

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  • Expression of Epiplakin1 in the developing and adult mouse retina Reviewed

    Tetsu Yoshida, Xiaoli Guo, Kazuhiko Namekata, Yoshinori Mitamura, Shoen Kume, Takayuki Harada

    JAPANESE JOURNAL OF OPHTHALMOLOGY   54 ( 1 )   85 - 88   2010.1

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    DOI： 10.1007/s10384-009-0751-y

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  • Identification of DAF1/CD55, a novel definitive endoderm marker Reviewed

    Nobuaki Shiraki, Seiko Harada, Soichiro Ogaki, Kazuhiko Kume, Shoen Kume

    Cell Structure and Function   35 ( 2 )   73 - 80   2010

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    DOI： 10.1247/csf.10004

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  • Conserved origin of the ventral pancreas in chicken Reviewed

    Kumi Matsuura, Keiichi Katsumoto, Kimiko Fukuda, Kazuhiko Kume, Shoen Kume

    MECHANISMS OF DEVELOPMENT   126 ( 10 )   817 - 827   2009.10

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    DOI： 10.1016/j.mod.2009.07.009

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  • Origin of pancreatic precursors in the chick embryo and the mechanism of endoderm regionalization Reviewed

    Keiichi Katsumoto, Kimiko Fukuda, Wataru Kimura, Kenji Shimamura, Sadao Yasugi, Shoen Kume

    MECHANISMS OF DEVELOPMENT   126 ( 7 )   539 - 551   2009.7

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    DOI： 10.1016/j.mod.2009.03.006

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  • Analysis of gene expressions of embryonic stem-derived Pdx1-expressing cells: Implications of genes involved in pancreas differentiation Reviewed

    Tetsu Yoshida, Kazuya Murata, Nobuaki Shiraki, Kazuhiko Kume, Shoen Kume

    DEVELOPMENT GROWTH & DIFFERENTIATION   51 ( 4 )   463 - 472   2009.5

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    DOI： 10.1111/j.1440-169X.2009.01109.x

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  • Differentiation and characterization of embryonic stem cells into three germ layers Reviewed

    Nobuaki Shiraki, Yuichiro Higuchi, Seiko Harada, Kahoko Umeda, Takayuki Isagawa, Hiroyuki Aburatani, Kazuhiko Kume, Shoen Kume

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS   381 ( 4 )   694 - 699   2009.4

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    DOI： 10.1016/j.bbrc.2009.02.120

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  • Expression patterns of epiplakin1 in pancreas, pancreatic cancer and regenerating pancreas Reviewed

    Tetsu Yoshida, Nobuaki Shiraki, Hideo Baba, Mizuki Goto, Sakuhei Fujiwara, Kazuhiko Kume, Shoen Kume

    GENES TO CELLS   13 ( 7 )   667 - 678   2008.7

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    DOI： 10.1111/j.1365-2443.2008.01196.x

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  • Differentiation of mouse and human embryonic stem cells into hepatic lineages Reviewed

    Nobuaki Shiraki, Kahoko Umeda, Naomi Sakashita, Motohiro Takeya, Kazuhiko Kume, Shoen Kume

    GENES TO CELLS   13 ( 7 )   731 - 746   2008.7

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    DOI： 10.1111/j.1365-2443.2008.01201.x

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  • Guided differentiation of embryonic stem cells into Pdx1-expressing regional-specific definitive endoderm Reviewed

    Nobuaki Shiraki, Tetsu Yoshida, Kimi Araki, Akihiro Umezawa, Yuichiro Higuchi, Hideo Goto, Kazuhiko Kume, Shoen Kume

    Stem Cells   26 ( 4 )   874 - 885   2008.4

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    DOI： 10.1634/stemcells.2007-0608

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  • Hyaline cartilage formation and enchondral ossification modeled with KUM5 and OP9 chondroblasts Reviewed

    Tadashi Sugiki, Taro Uyama, Masashi Toyoda, Hideo Morioka, Shoen Kume, Kenji Miyado, Kenji Matsumoto, Hirohisa Saito, Noriyuki Tsumaki, Yoriko Takahashi, Yoshiaki Toyama, Akihiro Umezawa

    JOURNAL OF CELLULAR BIOCHEMISTRY   100 ( 5 )   1240 - 1254   2007.4

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    DOI： 10.1002/jcb.21125

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  • Autophagic cell death of pancreatic acinar cells in serine protease inhibitor Kazal type 3-deficient mice Reviewed

    Masaki Ohmuraya, Masahiko Hirota, Masatake Araki, Noboru Mizushima, Makoto Matsui, Takao Mizumoto, Kyoko Haruna, Shoen Kume, Motohiro Takeya, Michio Ogawa, Kimi Araki, Ken-Ichi Yamamura

    Gastroenterology   129 ( 2 )   696 - 705   2005.8

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    DOI： 10.1016/j.gastro.2005.05.057

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  • Review: Stem-cell-based approaches for regenerative medicine Reviewed

    Shoen Kume

    Development Growth and Differentiation   47 ( 6 )   393 - 402   2005.8

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  • Review: The molecular basis and prospects in pancreatic development Reviewed

    Shoen Kume

    Development Growth and Differentiation   47 ( 6 )   367 - 374   2005.8

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  • Dopamine is a regulator of arousal in the fruit fly Reviewed

    K Kume, S Kume, SK Park, J Hirsh, FR Jackson

    JOURNAL OF NEUROSCIENCE   25 ( 32 )   7377 - 7384   2005.8

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    DOI： 10.1523/JNEUROSCI.2048-05.2005

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  • TGF-beta signaling potentiates differentiation of embryonic stem cells to Pdx-1 expressing endodermal cells Reviewed

    N Shiraki, CJ Lai, Y Hishikari, S Kume

    GENES TO CELLS   10 ( 6 )   503 - 516   2005.6

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    DOI： 10.1111/j.1365-2443.2005.00854.x

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  • Enhanced expression of PDX-1 and Ngn3 by exendin-4 during beta cell regeneration in STZ-treated mice Reviewed

    S Kodama, T Toyonaga, T Kondo, K Matsumoto, K Tsuruzoe, J Kawashima, H Goto, K Kume, S Kume, M Sakakida, E Araki

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS   327 ( 4 )   1170 - 1178   2005.2

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    DOI： 10.1016/j.bbrc.2004.12.120

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  • Calcium/calmodulin-dependent protein kinase I in Xenopus laevis Reviewed

    T Saneyoshi, S Kume, K Mikoshiba

    COMPARATIVE BIOCHEMISTRY AND PHYSIOLOGY B-BIOCHEMISTRY & MOLECULAR BIOLOGY   134 ( 3 )   499 - 507   2003.3

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    DOI： 10.1016/S1096-4959(02)00292-0

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  • Rapid analysis of protein interactions: On-chip micropurification of recombinant protein expressed in Esherichia coli Reviewed

    Tohru Natsume, Masato Taoka, Hiroshi Manki, Shouen Kume, Toshiaki Isobe, Katsuhiko Mikoshiba

    Proteomics   2 ( 9 )   1247 - 1253   2002.9

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    DOI： 10.1002/1615-9861(200209)2:9<1247::AID-PROT1247>3.0.CO;2-V

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  • The Wnt/calcium pathway activates NF-AT and promotes ventral cell fate in Xenopus embryos Reviewed

    T Saneyoshi, S Kume, Y Amasaki, K Mikoshiba

    NATURE   417 ( 6886 )   295 - 299   2002.5

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    DOI： 10.1038/417295a

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  • Molecular cloning and expression profile of Xenopus calcineurin A subunit Reviewed

    Takeo Saneyoshi, Shoen Kume, Tohru Natsume, Katsuhiko Mikoshiba

    Biochimica et Biophysica Acta - Molecular Cell Research   1499 ( 1-2 )   164 - 170   2000.12

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    DOI： 10.1016/S0167-4889(00)00083-5

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  • G alpha s family G proteins activate IP3-Ca2+ signaling via G beta gamma and transduce ventralizing signals in Xenopus Reviewed

    S Kume, T Inoue, K Mikoshiba

    DEVELOPMENTAL BIOLOGY   226 ( 1 )   88 - 103   2000.10

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    DOI： 10.1006/dbio.2000.9849

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  • Desensitization of IP3-induced Ca2+ release by overexpression of a constitutively active Gqα protein converts ventral to dorsal fate in Xenopus early embryos Reviewed

    Shoen Kume, Takeo Saneyoshi, Katsuhiko Mikoshiba

    Development Growth and Differentiation   42 ( 4 )   327 - 335   2000

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    DOI： 10.1046/j.1440-169X.2000.00519.x

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  • Role of the inositol 1,4,5-trisphosphate receptor in early embryonic development Reviewed

    S. Kume

    Cellular and Molecular Life Sciences   56 ( 3-4 )   296 - 304   1999.10

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  • Role of IP3 receptor/Ca2+ channel on egg and embryo development

    Katsuhiko Mikoshiba, Shoen Kume, Akira Muto

    Zygote   6 ( 1 )   S56   1998

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  • Inositol 1,4,5-trisphosphate receptor mediates ventralising signals in Xenopus embryos

    Kume Shoen, Muto Akira, Okano Hideyuki, Mikoshiba Katsuhiko

    Zygote   6 ( 1 SUPPL. )   1998

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  • Developmental expression of the inositol 1,4,5-trisphosphate receptor and localization of inositol 1,4,5-trisphosphate during early embryogenesis in Xenopus laevis Reviewed

    Shoen Kume, Akira Muto, Hideyuki Okano, Katsuhiko Mikoshiba

    Mechanisms of Development   66 ( 1-2 )   157 - 168   1997.8

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    DOI： 10.1016/S0925-4773(97)00101-9

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  • Activation of the G protein Gq/11 through tyrosine phosphorylation of the α subunit Reviewed

    Hisashi Umemori, Takafumi Inoue, Shoen Kume, Naohiro Sekiyama, Motoshi Nagao, Hiroshi Itoh, Shigetada Nakanishi, Katsuhiko Mikoshiba, Tadashi Yamamoto

    Science   276 ( 5320 )   1878 - 1881   1997.6

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    DOI： 10.1126/science.276.5320.1878

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  • Developmental expression of the inositol 1,4,5-trisphosphate receptor and structural changes in the endoplasmic reticulum during oogenesis and meiotic maturation of Xenopus laevis Reviewed

    Shoen Kume, Akitsugu Yamamoto, Takafumi Inoue, Akira Muto, Hideyuki Okano, Katsuhiko Mikoshiba

    Developmental Biology   182 ( 2 )   228 - 239   1997.2

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    DOI： 10.1006/dbio.1996.8479

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  • G(q) pathway desensitizes chemotactic receptor-induced calcium signaling via inositol trisphosphate receptor down-regulation Reviewed

    Z. I. Honda, T. Takano, N. Hirose, T. Suzuki, A. Muto, S. Kume, K. Mikoshiba, K. Itoh, T. Shimizu

    Journal of Biological Chemistry   270 ( 9 )   4840 - 4844   1995

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    DOI： 10.1074/jbc.270.9.4840

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  • ANTISENSE INTERVENTION OF GENE-EXPRESSION Reviewed

    K MIKOSHIBA, H OKANO, J ARUGA, S KUME, A MUTO

    JOURNAL OF NEUROCHEMISTRY   63   S14 - S14   1994

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  • The Xenopus IP3 receptor: Structure, function, and localization in oocytes and eggs Reviewed

    Shoen Kume, Akira Muto, Jun Aruga, Toshiyuki Nakagawa, Takayuki Michikawa, Teiichi Furuichi, Shinji Nakade, Hideyuki Okano, Katsuhiko Mikoshiba

    Cell   73 ( 3 )   555 - 570   1993.5

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    DOI： 10.1016/0092-8674(93)90142-d

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  • STRUCTURE AND FUNCTION OF INOSITOL 1,4,5-TRISPHOSPHATE RECEPTOR

    K MIKOSHIBA, T FURUICHI, A MIYAWAKI, S YOSHIKAWA, S NAKADE, T MICHIKAWA, T NAKAGAWA, H OKANO, S KUME, A MUTO, J ARUGA, N YAMADA, Y HAMANAKA, FUJINO, I, M KOBAYASHI

    MOLECULAR BASIS OF ION CHANNELS AND RECEPTORS INVOLVED IN NERVE EXCITATION, SYNAPTIC TRANSMISSION AND MUSCLE CONTRACTION   707   178 - 197   1993

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MISC

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Presentations

  • Can we turn ES cells into pancreatic beta cells?

    11th iCeMS international Symposium 、2011年 

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  • Signals involved in guiding ES cells to differentiate into pancreatic beta cel

    UNIA WORKSHOP 2011"LIVER AND PANCREAS: FROM DEVELOPMENT TO DISEAS”、2011年 

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  • 多能性幹細胞から膵β細胞への分化研究の最近の進歩

    日常診療に役立つ熊本代謝・内分泌研究会、2011年 

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  • 多能性幹細胞を用いた肝・膵への分化誘導研究

    東京医科歯科大学 難治疾患共同研究拠点事業による研究集会『器官発生の分子機構解明と疾患克服への基盤的理解』、2011年 

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  • 多能性幹細胞を用いた膵臓の再生医療研究

    熊本大学医学部付属病院 臨床カンファレンス、2013年 

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  • Signals guiding pluripotent stem cells into pancreatic beta cells.

    Beta Cell Workshop 、2013年 

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  • ES細胞から膵臓β細胞と腸への分化誘導研究

    塩野義探索研究所、2013年 

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  • 膵β細胞の分化を制御するシグナル

    日本薬理学会、2013年 

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  • 多能性幹細胞を用いた膵臓の発生分化と再生研究

    第21回 北野糖尿病・内分泌?楽部、2012年 

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  • 多能性幹細胞を用いた消化器系細胞の発生再生研究

    浜松医科大学大学院特別講演、2012年 

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  • 多能性幹細胞を使った夢の再生医療〜糖尿病の再生医療〜

    高校生のための熊大ワクワク連続講義、2012年 

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  • 最先端の生命科学研究教育拠点としての取組

    くまもと医療都市ネットワーク懇話会、2012年 

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  • 消化器官の発生と再生：幹細胞からのアプローチ

    細胞生物学信州夏期研究会 、2012年 

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  • 多能性幹細胞から膵臓β細胞への分化誘導研究

    第一三共株式会社セミナー、2012年 

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  • ES/iPS細胞が拓く未来の再生医療

    日本薬学会 市民公開講座、2014年 

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  • 多能性幹細胞を用いた膵β細胞の分化誘導研究

    第一回Cardiology Metabolism Endocrinology Nephrology Conference (CARMEN conference)、2014年 

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  • 多能性幹細胞を用いた膵β細胞の再生医学研究

    長崎大学 脳病態治療シンポ、2014年 

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  • iPS細胞と夢の再生医学

    熊本同友会、2014年 

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  • 膵β細胞の再生医療と糖尿病治療への応用

    Islet Equality 座談会、2014年 

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  • 熊大におけるiPS細胞研究の現状について

    熊杏会八代支部総会、2013年 

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  • 多能性幹細胞を用いた膵β細胞への分化誘導研究

    第3回細胞再生医療研究会、2013年 

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  • 多能性幹細胞を用いた膵β細胞の発生再生研究

    内分泌代謝学サマーセミナー、2013年 

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  • Screening for low molecular compounds that potentiate beta cell differentiation.

    Canada-Japan Stem Cell Workshop， ISSCR 、2013年 

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  • 多能性幹細胞から膵β細胞への分化を制御するシグナル

    第56回日本糖尿病学会年次学術集会総会、2013年 

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  • 多能性幹細胞を用いた再生医療研究

    基盤医学特論 名古屋大学、2014年 

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  • Signals that control differentiation of ES/iPS cells into pancreatic beta cells

    The 8th International Conference on Cell Therapy、2014年 

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  • 多能性幹細胞モデルを用いた膵臓の発生分化研究

    第87回日本生化学会大会、2014年 

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  • iPS技術を用いた膵β細胞の分化誘導研究

    第29回日本糖尿病合併症学会、2014年 

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  • ト多能性幹細胞を用いた消化器官の発生再生と創薬研究

    熊本大学医学部第一内科同門会同窓会、2014年 

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  • 多能性幹細胞から消化器官を創る

    New Insights of Molecular Genetics on Growth Disorders、2014年 

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  • Chemical genetic identification of signals that control late-stage pancreatic beta cell differentiation.

    ISSCR, 2014年 

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  • Signals that control differentiation of pluripotent stem cells into pancreatic beta cells

    TERMIS-EU4、2014年 

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  • 膵β細胞再生研究の最前線

    第57回糖尿病学会年会、2014年 

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  • 再生医療を用いた糖尿病治療の今後の展望

    日本内分泌学会学術総会、2014年 

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  • The role of extracellular matrices in guiding ES/iPS cell differentiation into hepatic or pancreatic cells

    The 11th US-Japan Symposium on Drug Delivery Systems、2011年 

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  • 多能性幹細胞を用いたβ細胞再生のアプローチ；Toward the road of beta cell regeneration cells

    The 2nd Diabetes Research Innovation Symposium、2015年 

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  • 多能性幹細胞を応用した膵β細胞の再生治療

    第67回 糖尿病血管障害講演会、2015年 

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  • 多能性幹細胞を用いた肝と膵の再生医学研究

    第22回肝細胞研究会年会、2015年 

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  • ヒトiPS細胞から機能的な膵島の創製

    IDDMシンポジウム、サイエンスカフェ、2015年 

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  • iPS細胞を用いた再生医療

    第27回福岡糖尿病アゴラ、2015年 

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  • 多能性幹細胞から消化器官への分化誘導

    『Frontiers in Medical Science Seminar Series #76慶応大医学部総合医科学研究センターセミナー、2015年 

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  • ヒト多能性幹細胞を用いた消化器官の発生再生と創薬研究

    鹿児島大学『医学研究講義』、2014年 

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  • 幹細胞と再生医学

    熊本県立第二高等学校SSH特別講演会、2014年 

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  • 女性研究者の育成?熊?の取り組み?

    『保育と行動経済学-学内保育園を通じて』、2014年 

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  • iPS細胞を用いた再生医療研究

    熊本県眼科医学会研修会、2014年 

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  • 多能性幹細胞を用いた膵β細胞の再生医療への展望

    千葉次世代糖尿病治療研究会、2016年 

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  • Pluripotent stem cells for modeling cellular biology, developmental biology and regenerative medicine

    第4回の生命理工国際シンポジウム、2016年 

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  • 多能性幹細胞を用いた消化器官の発生再生研究

    東京工業大学 大学院生命理工学研究科 研究科セミナー、2016年 

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  • 多能性幹細胞を用いた膵の再生医学と創薬への展開

    鹿児島大学『医学研究講義』、2016年 

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  • 多能性幹細胞の多能性維持および分化におけるアミノ酸およびその誘導体の役割

    BMB2015ワークショップ、2015年 

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  • 幹細胞生物学（ES細胞とiPS細胞）

    東京工業大学 高校生のための生命理工レクチャー（ガードナー国際賞受賞記念講演会）、2015年 

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  • 多能性幹細胞を用いた消化器官の分化誘導研究

    第4回細胞治療研究会、2015年 

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  • ES/iPS細胞を用いた糖尿病の創薬研究

    Bio Japan、2015年 

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  • 多能性幹細胞を用いた膵β細胞の再生治療

    第15回Islet Biology 研究会、2015年 

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  • iPS cell development in Japan〜toward the cure of diabetes 〜

    Roster of Researchers Lecturing for The 7th YCU Science Summer Program 、2015年 

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  • 多能性幹細胞を用いた糖尿病の再生医学の展望〜ライフワークバランスで人生も研究も楽しく！〜

    第50回日本小児内分泌学会学術集会 2016年 

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  • Generation of insulin-producing β-like cells from human iPS cells

    11th IDF WPR & 8th AASD meeting、2016年 

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  • 多能性幹細胞の分化制御と代謝

    細胞生物学会年会 2016年 

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  • 多能性幹細胞から膵β細胞への分化誘導」白木伸明「アミノ酸代謝制御による幹細胞の未分化性維持と分化促進

    バイオインダストリー協会勉強会、2016年 

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  • 多能性幹細胞を応用した糖尿病の再生治療

    第10回桜山糖尿病と網膜症研究会、2016年 

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  • 多能性幹細胞から膵β細胞への分化誘導

    第15回日本再生医療学会総会、2016年 

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  • 糖尿病の創薬研究と再生医療へ向けたヒトiPS細胞の分化制御方法の開発

    疾患特異的iPS細胞を活用した難病研究班の勉強会、2016年 

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  • 多能性幹細胞を用いた糖尿病の再生治療のアプローチ

    第43回日本膵・膵島移植研究会、2016年 

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  • 多能性幹細胞を用いた糖尿病の再生・創薬研究

    第?回研究所セミナー 国立国際医療研究センター、2016年 

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  • 多能性幹細胞を使った消化器官の再生医療への取組み

    第19回再生医療の実用化に関するニーズ発表会、2016年 

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  • 膵臓の再生医学と幹細胞研究

    三共株式会社セミナー、2007年 

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  • Directed differentiation of ES cells into pancreatic progenitors

    第８回インスリンリサーチフォーラム、2006年 

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  • Signals that regulate beta cell differentiation and beta cell mass.

    American Diabetes Association’s (ADA) 77 th Scientific Sessions 

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  • Directed differentiation of ES cells into endoderm cell lineages

    ３９回日本発生生物学会、2006年 

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  • 多能性幹細胞から膵β細胞を創る：代謝とエピゲノムによる制御

    エピジェネティック研究会年会 2017年 

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  • ES細胞を用いた膵臓の再生医学の現状と展望

    第49回日本糖尿病学会年次学術集会、2006年 

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  • 多能性幹細胞を用いた膵の発生再生研究

    日本解剖学会総会・全国学術集会 

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  • ES細胞から内胚葉系譜への分化誘導

    ジョイントフォーラム 京大再生研、2006年 

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  • 多能性幹細胞から膵β細胞への分化誘導の技術開発

    第5回 Islet E-quility Meeting 2017年 

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  • ES細胞から膵幹細胞へ分化誘導方法の開発―膵臓の再生医学―

    第20回熊本県産学官技術交流会、2006年 

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  • 多能性幹細胞の分化制御における培地組成の重要性 〜メチオニン除去培地を利用した分化制御〜

    再生医療学会年会 2017年 

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  • 膵の発生分化と幹細胞系を用いた膵の再生医学

    第５２回日本臨床検査医学会総会第４５回日本臨床化学会年会連合大会、2005年 

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  • 多能性幹細胞からの肝細胞の作製と利用

    第4回霧島会議 2017年 

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  • In vitro differentiation of ES cells into Pdx-1 expressing Endodermal cells

    International Symposium on Dynamics o of Developmental systems、2005年 

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  • 多能性幹細胞を用いた膵β細胞への分化誘導研究〜再生医療と創薬への展望〜

    第13回山口糖尿病フォーラム 2017年 

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  • ES細胞からの膵細胞分化

    第23回炎症再生学会、2002年 

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  • 多能性幹細胞を用いた消化器官の分化誘導研究〜再生医療と創薬への展望〜

    セミナー2017年 

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  • マウスES細胞から膵臓の分化誘導

    第35回日本発生生物学会大会 

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  • How can we generate functional beta cells?

    The Japan Diabetes Innovation Summit、2016 

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  • 多能性幹細胞から膵臓β細胞を創る

    「細胞を創る」研究会9.0 年会 2017年 

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  • 消化器系細胞へのES細胞の分化誘導

    埼玉医科大学 ゲノム医学研究センター 卒後教育委員会後援学術集会、2008年 

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  • ES細胞を用いた消化器官の分化誘導

    第29回日本炎症・再生医学会、2008年 

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  • 多能性幹細胞から膵β細胞への分化誘導と再生医療への展望

    第7回日本マーモセット研究会 2018年 

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  • ES細胞を用いた消化器官の発生と再生医学研究

    国立環境研究所セミナー、2008年 

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  • Generating pancreatic beta cells from ES and iPS cells

    International Diabetes Federation (IDF） 2017 

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  • 消化器系の再生医学研究の現状と展望

    熊杏会総会・評議員会、2008年 

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  • ヒトiPS細胞から肝臓細胞への新規分化誘導系の構築、および初代培養肝細胞との機能比較

    生命科学系学会合同年次大会 2018年 

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  • 消化器系へのES細胞の分化誘導と医学応用

    第7回日本再生医療学会 、2008年 

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  • モノアミンによるヒト膵β細胞分化および成熟化の調節機能を解明

    生命科学系学会合同年次大会 2018年 

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  • ES細胞を用いた発生分化再生研究

    武田薬品工業（株）医薬研究本部開拓研究所再生情報交換会 、2007年 

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  • 膵β細胞発生におけるモノアミンシグナル伝達経路の解明

    生命科学系学会合同年次大会 2018年 

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  • ES細胞から膵幹細胞の分化誘導

    薬剤学懇話会、2007年 

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  • 多能性幹細胞から膵β細胞への分化誘導制御シグナル

    第3回生体調節研究所内分泌代謝シンポジウム 2017年 

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  • Xenopus and ES cells as tools for developmental biology

    国際シンポジウム「バイオサイエンスの最前線」、2007年 

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  • 多能性幹細胞を用いた糖尿病の再生医学研究

    LIP．横浜オープンイノベーションカンファレンス2017年 

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  • 膵臓の発生分化研究〜ES細胞からのアプローチ〜

    帯刀益夫教授 退官記念シンポジウム「細胞分化と発生」、2007年 

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  • ヒトiPS細胞由来膵臓β細胞の作製と再生医療に使えるための技術開発

    第4回再生・細胞医療産業化促進セミナー 2017年 

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  • ES cells as a tool for developmental biology and regenerative medicine of pancrea

    International Workshop on Bioelectronics、2007年 

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  • Chemical and metabolic control of pluripotent stem cell differentiation into pancreatic β cells

    GRE External seminar, Dundee University、2017年 

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  • Generation of functional mature insulin-producing cells from induced pluripotent stem cells.

    5th Gifu Innovation Lecture Symposimum, 2017年 

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  • Differentiation of ES cells into pancreatic and hepatic cells

    ISREC seminar、2009年 

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  • ES・iPS細胞から消化器官細胞への分化誘導研究

    第49回先天異常学会、2009年 

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  • Stem cells differentiation into Pancreatic and Hepatic Lineages.

    Bioelectrics Seminar 、2009年 

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  • 幹細胞を用いた消化器官の再生医学研究

    第112回日本小児科学会学術集会、2009年 

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  • Application of multipotent stem cells for the regeneration of digestive tissue cells

    第8回日本再生医療学会、2009年 

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  • 幹細胞を用いた消化器系の発生再生研究

    5th Annual Meeting of Miyazaki Science Camp. 、2009年 

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  • 消化器系細胞への多能性幹細胞の分化誘導

    発生研再生研ＣＤＢ慶応ジョイントフォーラム、2009年 

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  • ES細胞・iPS細胞・そして夢の再生医学

    第3回熊本大学 ホームカミングデー、2008年 

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  • Guided differentiation of ES cells into pancreatic and hepatic lineages

    Academia Sinica Seminar、2008年 

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  • ES細胞から消化器系細胞の分化誘導

    独立行政法人・医薬基盤研究所セミナー 、2008年 

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  • Guiding ES/iPS cells to differentiate into pancreatic beta cells

    第43回発生生物学会 、2010年 

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  • ES/iPS細胞から膵細胞系譜への分化誘導

    第53回日本糖尿病学会年次学術集会、2010年 

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  • The Guided differentiation of ES cells into the pancreatic lineage

    ice、2010年 

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  • ES/iPS細胞から膵と肝への分化誘導研究

    京都大学再生研セミナー、2010年 

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  • 幹細胞を用いた膵β細胞の再生医学研究の現状

    日本IDDMネットワークシンポジウム、2010年 

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  • 幹細胞を用いた消化器官細胞への分化誘導

    第15回大阪大学医療組織工学フォーラム、2009年 

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  • ES/iPS細胞を用いた消化器官細胞への分化誘導

    慶応大学医学部セミナー、2009年 

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  • 膵臓の分化誘導

    日本生化学会年会、2009年 

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  • 幹細胞から消化器官細胞への分化誘導

    産総研セミナー、2009年 

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  • 幹細胞を用いた消化器官の発生再生研究

    第33回阿蘇シンポジウム、2009年 

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  • ヒトiPS細胞から膵臓β細胞への分化誘導の技術開発

    日本糖尿病学会年会 2018年 

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  • 代謝による多能性幹細胞の分化制御

    第6回がんと代謝研究会 2018年 

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  • 多能性幹細胞から膵β細胞への分化制御

    第91回日本内分泌学会年会 2018年 

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  • 多能性幹細胞から膵β細胞への分化研究

    東京インスリン分泌研究会、2011年 

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  • Signals involved in guiding ES cells to differentiate into pancreatic beta cells

    KEY Forum in Developmental Biology and Regenerative Medicine、2011年 

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  • ヒトiPS細胞から膵β細胞の分化誘導」

    最先端・次世代研究開発プログラムキックオフシンポジウム、2011年 

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  • ES/iPS細胞から肝への分化誘導

    日本組織培養学会第84回大会 日本組織培養学会-動物実験代替法学会、2011年 

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  • 膵β細胞の分化と再生研究

    シオノギ創薬イノベーションセンターセミナー、2011年 

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  • 多能性幹細胞から膵臓と肝臓への分化誘導

    同仁化学研究所セミナー、2011年 

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  • 幹細胞を用いた消化器官の再生医学と創薬への利用

    鹿児島大学「FSRC先端医療開発分野セミナー、2011年 

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  • ES/iPS細胞の分化誘導をサポートする細胞外環境の重要性

    PartIII 再生医療を支える「モノづくり」の力〜細胞の基礎生物医学研究から再生誘導治療、そして創薬開発まで、2010年 

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  • 糖尿病と再生医学

    くまもと県民カレッジリレー講座「キャンパスパレア」、2010年 

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  • 膵臓･肝臓の再生医療と創薬への応用

    Walk Again 、2010年 

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  • 多能性幹細胞から膵β細胞への分化誘導研究

    第59回日本実験動物学会、2012年 

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  • Signals guiding differentiation of pluripotent stem cells into pancreatic beta cells

    第55回日本糖尿病学会、2012年 

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  • 多能性幹細胞の分化をサポートする細胞外環境

    日本組織培養学会JTCA第85回大会、2012年 

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  • ES/iPS細胞からβ細胞への分化誘導

    日本内分泌学会総会、2012年 

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  • iPS細胞を用いた糖尿病治療について

    日本小児科学会、2012年 

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Research Projects

  • Generation of iPS-derived beta cells with heterogeneity

    Grant number：24K02501  2024.4 - 2027.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (B)

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    Grant amount：\18590000 （ Direct Cost: \14300000 、 Indirect Cost：\4290000 ）

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  • iPS細胞由来β細胞を活用した革新的移植デバイスを用いた糖尿病治療法の開発

    Grant number：24ym0126801j0003  2024.4 - 2025.3

    AMED  橋渡し研究プログラム事業 「オープンアクセス型拠点を活用した革新的医療技術の持続的創出」の取り組み 

    白木伸明, 粂昭苑, 藤枝俊宣

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    Grant type：Competitive

    Grant amount：\3636364 （ Direct Cost: \3636364 ）

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  • Improvement of functionality by heterogeneity formation of the iPS-derived pancreatic beta cells

    Grant number：22K19543  2022.6 - 2024.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Challenging Research (Exploratory)

    Kume Shoen

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    Grant amount：\6500000 （ Direct Cost: \5000000 、 Indirect Cost：\1500000 ）

    We identified TH (dopamine synthase) as a candidate gene involved in heterogeneity in mouse pancreatic β cells. To examine the underlying molecular mechanism of the heterogeneity of beta cells, we performed forced expression of TH in mouse pancreatic β cells. We mixed it with normal pancreatic islet cells at a certain ratio. We then evaluated pancreatic islets' glucose-stimulated insulin secretion (GSIS) ability with or without overexpressing TH. As a result, we found that overexpression of TH in the beta cells lowered the GSIS ability. However, pancreatic islets containing a certain proportion of islet cells expressing TH maintained their GSIS ability for longer. From this result, We therefore concluded that heterogeneity confers pancreatic β cells to preserve their function.

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  • Elucidation of the molecular mechanism regulating pancreatic islets using human pluripotent stem cell differentiation system

    Grant number：21H02978  2021.4 - 2024.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (B)

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    Grant amount：\17290000 （ Direct Cost: \13300000 、 Indirect Cost：\3990000 ）

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  • The mechanism for the maintenance of pancreatic beta cells derived by in vitro differentiation of human pluripotent stem cells

    Grant number：18H02861  2018.4 - 2021.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (B)

    Kume Shoen

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    Grant amount：\17290000 （ Direct Cost: \13300000 、 Indirect Cost：\3990000 ）

    VMAT2 plays a significant negative regulatory role in the transmission of dopamine. βVMAT2KO beta cells (or WT beta-cells treated with VMAT2 inhibitor TBZ) cannot uptake dopamine into vesicles; thus, dopamine is subjected to degradation by MAO, leading to a reduced dopamine content and an increased generation of ROS. The decreased dopamine content leads to a reduction in the dopamine negative feedback loop which, in turn, leads to elevated insulin secretion. Under HFD conditions, where excess nutrient stress exists, insulin secretion occurs frequently, increasing beta-cell exposure to ROS. Long-term exposure to ROS leads to increased vulnerability of βVMAT2KO beta-cells and accelerated beta-cell failure. βVMAT2KO beta-cells show an initial compensation via beta-cell growth and increased beta-cell mass followed by dedifferentiation and beta-cell death, which is a characteristic of the progression of beta-cell failure.

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  • Research on innovative cell transplantation device using immunoisolation membrane

    Grant number：16K01362  2016.4 - 2019.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (C)

    Ando Yusuke, Nakaji Shuhei, Kobayashi Goro

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    Grant amount：\4680000 （ Direct Cost: \3600000 、 Indirect Cost：\1080000 ）

    The formation of a semipermeable membrane made of ethylene-vinyl alcohol copolymer to be used for a cell transplantation device was investigated, and it became possible to stably produce membranes with different pore sizes. The permeability of glucose and various proteins was examined using membranes with different pore sizes, and it was clarified that separation of proteins is possible by pore size. We found a membrane impermeable to IgG, indicating the possibility of protecting antibody permeation. Furthermore, it was confirmed that cells did not permeate through any of the membranes. On the other hand, for the evaluation of cells, preparation of pancreatic β cells from human iPS cells was performed, and evaluation was performed to confirm that the prepared pancreatic β cells secrete insulin depending on high concentration of glucose. The cells were enclosed in a device and transplantation to animals was also attempted.

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  • Identification of hepatic maturation mechanisms of human iPS cells by using chemical screening

    Grant number：26893201  2014.8 - 2015.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Research Activity Start-up

    YAMAZOE Taiji, KUME Shoen, SHIRAKI Nobuaki, SASAKI Yutaka

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    Grant amount：\1430000 （ Direct Cost: \1100000 、 Indirect Cost：\330000 ）

    The chemical screening were carried out for the identification of candidate drug that potentiates hepatic maturation of human iPS derived cells. We obtained the candidate reagent that increases mature hepatocyte marker, Albumin positive cells and decreases immature hepatocyte marker, AFP positive cells. This candidate drug will give us the new aspects of hepatic maturation mechanisms, based on the knowledge of its molecular targets and their down stream molecules. This candidate drug is available in clinic, so that it might be possible to utilize this candidate drug for inducing a maturation of human iPS derived hepatocytes without toxic effects of drugs.

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  • Generation of human iPS-derived pancreatic beta cells and its application towards regenerative medicine

    Grant number：26253059  2014.4 - 2017.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (A)

    Kume Shoen

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    Grant amount：\41340000 （ Direct Cost: \31800000 、 Indirect Cost：\9540000 ）

    Through screening and analysis of small molecular compound that potentiated differentiation of human induced pluripotent stem (hiPS) cells into pancreatic beta cells, we found that activation of Wnt signal increased beta cell differentiation in hiPS cells, and that our previously identified VMAT2-monoamine as a negative regulator for pancreatic differentiation, also applied to hiPS cells. We also identified domperidone (DPD), a dopamine D2 receptor (DRD2) antagonist, as a compound that enhances beta cell mass. In adult islet dissociation cultures, beta cell loss occurs through dedifferentiation, which was prevented by DPD. Dopamine modulates beta cell mass through DRD2 and exerts an inhibitory effect on adenosine signaling, a previously identified beta cell mass positive regulator. We believe that our knowledge on regulation of beta cell differentiation and cell mass regulation would be profitable for future manipulation of hiPS-derived beta cells.

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  • The purification and expansion of human iPS cell-derived intestinal precursor cells for future application in regenerative medicine

    Grant number：26670384  2014.4 - 2016.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Challenging Exploratory Research

    Kume Shoen

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    Grant amount：\3640000 （ Direct Cost: \2800000 、 Indirect Cost：\840000 ）

    We established a cost effective protocol to induce endoderm differentiation with low concentration of Activin by adding DMSO. We found that at the presence of DMSO, the threshold of Activin to induce intestinal differentiation is much reduced. We also established a protocol to selectively culture the human iPS cells-derived intestinal epithelial cells from a mixed cell population, so that the purified cells could be expanded and used for further studies. We also found that using defined growth factors and chemicals, the purified cells could be expanded and further matured. The present studies therefore enabled us to prepare a certain amount of cells that could be used for further studies for establishing regenerative medicine of the intestine.

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  • 膵幹細胞の分化と維持の制御機構

    Grant number：21390280  2009 - 2011

    日本学術振興会  科学研究費助成事業  基盤研究(B)

    粂 昭苑

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    Grant amount：\17810000 （ Direct Cost: \13700000 、 Indirect Cost：\4110000 ）

    本研究では、ES/iPS細胞から膵臓系譜への発生途上のモデル細胞、膵臓の体性幹細胞のモデル細胞を基軸とし、正常発生分化・再生過程と常に比較しながら、細胞の内因性プログラムの変危化、分化誘導シグナルの同定、幹細胞の自己複製と分化制御機構(「ニッチ」)解明を目指す。
    1.汎腸管内胚葉の細胞表層マーカーとしてのDaf1(CD55)の発見およびその解析
    これまでにES細胞由来の内胚葉の解析により、Daf1(CD55)を同定した。CD55+/E-cadherin+細胞はCxcr4+/E-cadherin+に比べて、成熟度の高い細胞集団であることがマイクロアレーおよび細胞培養の結果により強くしさせれた。
    2.膵臓の再生・修復における体性幹細胞の同定、遺伝子発現、機能解析
    これまでに申請者らが、ES細胞由来のモデル細胞において、Epiplakin1(Eppk1)遺伝子を膵幹細胞マーカー候補遺伝子として同定した(Yoshida T et al.,2008)。Eppk1遺伝子はマウス胎仔Pdxl陽性の膵前駆細胞、Ngn3陽性膵内分泌前駆細胞、Ptfla陽性膵外分泌前駆細胞、成体腺房中心細胞で発現している(Yoshida T et al.,2008)。また、膵障害モデルにおいてEppk1が成体の膵幹細胞の指標となることが強く示唆された。この遺伝子が膵臓のみでなく、肝内胆管で発現しており、肝障害モデルにおいて一過性に現れるOval細胞においても発現することを明らかにした(Matsuo et al.,2011)。Eppk1遺伝子発現を追跡できる, Eppk1-CreERマウスを作成し、レポータマウスとの交配を完了した。今後この遺伝子の発現を追跡することで、肝臓と膵臓の成体前駆細胞を追跡できる。

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  • Hepatocyte replacement therapy for familial amybidotic polyneuropathy combining iPS cells and gene-repair therapy

    Grant number：21390270  2009 - 2011

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (B)

    ANDO Yukio, KUME Shoen, JONO Hirofumi, UEDA Mitsuharu, SHIRAKI Nobuaki

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    Grant amount：\18330000 （ Direct Cost: \14100000 、 Indirect Cost：\4230000 ）

    From April, 2009 to March, 2012, to develop a curative treatment for familial amyloidotic polyneuropathy(FAP), we obtained somatic cells from FAP patients or transgenic rats possessing a human ATTR V30M gene(ATTR V30M Tg rats) and reprogrammed to pluripotency to generate FAP-specific induced pluripotent stem(iPS) cells, and evaluated the possibility of hepatocyte replacement therapy combining FAP-specific iPS cells and gene-repair therapy using single stranded oligonucleotides(SSOs). In the next project, we will focus on using these FAP-specific iPS cells to elucidate the precise pathogenesis of FAP, improve the efficiency of gene conversion rate, and determine the availability of hepatocyte replacement therapy in the in vivo experiments using ATTR V30M Tg rats, an existing useful FAP animal model.

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  • Analysis of the pancreas regionalization factor in the pre-pancreas region.

    Grant number：20790652  2008 - 2009

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Young Scientists (B)

    KATSUMOTO Keiichi, KUME Shoen, FUKUDA Kimiko, SHIMAMURA Kenji, YASUGI Sadao

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    Grant amount：\4290000 （ Direct Cost: \3300000 、 Indirect Cost：\990000 ）

    To study the developmental origin of the pancreas we used DiI crystals to mark regions of the early chick endoderm: this allowed correlations to be established between specific endoderm sites and the positions of their descendants. Endodermal precursor cells for the stomach, pancreas and intestine were found to segregate immediately after completion of gastrulation. Transplantation experiments showed that region-specific endodermal fates are determined sequentially in the order stomach, intestine, and then pancreas. Non-pancreatic endoderm transplanted to the stomach region generated ectopic pancreas expressing both insulin and glucagon. These results imply that a pancreas-inducing signal is emitted from somitic mesoderm underlying the pre-pancreatic region, and this extends rostrally beyond the stomach endoderm region at the early somite stage. Transplantation experiments revealed that the endoderm responding to these pancreatic-inducing signals lies within the pre-pancreatic region and extends caudally beyond the region of the intestinal endoderm. The results indicate that pancreatic fate is determined in the area of overlap between these two regions.

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  • 消化器の形態形成に関わる遺伝子の解析

    Grant number：18659210  2006 - 2007

    日本学術振興会  科学研究費助成事業  萌芽研究

    粂 昭苑

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    Grant amount：\3300000 （ Direct Cost: \3300000 ）

    本研究では、マウスの消化管形成プログラムを進化発生学的なアプローチで明らかにしようとする試みである。特にカタユウレイボヤ、ニワトリ、マウスを用いて解析を行う。これらの動物モデルを使用することにより、消化器形成に関わる遺伝子群をゲノムワイドに探索・比較するものである。
    'カタユウレイボヤを用いた内胚葉系譜の遺伝子発現解析
    カタユウレイボヤを用いた内胚葉系譜の遺伝子発現解析 カタユウレイボヤの32細胞期の予定内胚葉(32細胞期胚のA6.1割球)を集め、マイクロアレイ(オリゴチップ)の解析を行った。対照実験として、32細胞期胚の予定神経索/脊索の細胞(32細胞期胚のA6.2割球)から抽出したRNAを用いたマイクロアレイを使用した。この中では、ある程度マウス初期胚の内胚葉で発現が遺伝子がオーバーラップしている。
    ニワトリに関しては、膵前駆細胞が出現する時期、出現する場所を細胞運命予定地図の作成により追跡し、決定した。また、今回の研究により、膵臓の分化誘導シグナルがどこから出されているかについて、予定膵臓を切り出し、胃、膵臓、あるいは腸への移植実験など発生学的に解析を行った結果、胃を裏打ちする中胚葉に膵臓誘導活性を有することを新たに見出した。これらの結果に基づき、膵への運命決定前後においての膵前駆細胞の内在性の変化、および分化誘導シグナルを捉えるために、各々内胚葉、中胚葉の胃、膵臓、小腸領域を切り出し、マイクロアレーを用いた遺伝子発現プロファイルを行った。
    マウス胚については、内胚葉の成立後、膵臓前駆細胞の遺伝子発現プロファイルのデータを海外の研究グループと共有できる状況にある。ES細胞を用いた試験管内分化誘導の系において、ES細胞由来の膵臓前駆細胞をセルソーターにより純化し、遺伝子網羅的発現解析を行った。ホヤ、ニワトリ、マウスで得られた遺伝子発現プロファイルの比較検討を行った。
    今後得られたプロファイルについて、有望な遺伝子についてさらに解析を進める予定である。

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  • 試験管内ES細胞分化誘導系を用いた膵幹細胞の解析

    Grant number：17045026  2005 - 2006

    日本学術振興会  科学研究費助成事業  特定領域研究

    粂 昭苑

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    Grant amount：\6000000 （ Direct Cost: \6000000 ）

    (計画)
    申請者らは、これまでにES細胞から内胚葉への分化誘導法を開発してきた。ES細胞から分化した膵幹細胞を蛍光蛋白の発現で可視化し、分化誘導する時の細胞の挙動を容易に追跡できるようにした。本プロジェクトでは、ES細胞から膵への細胞系譜の決定、膵幹細胞の性質を理解することを目指し、研究を進めた。その結果、以下の点を明らかにした。
    1、マウスES細胞から膵幹細胞の誘導に関わるシグナルの同定
    前年度では、ES細胞から膵臓に至るまでの分化誘導の過程を、ES細胞から中内胚葉、中内胚葉から内胚葉、内胚葉から膵前駆細胞へと3段階に分けて、それぞれの段階において分化誘導に関わる成長増殖分子及びその作用機序を明らかにした(Shirakiら論文投稿中)。すなわち、アクチビンと塩基性FGFがそれぞれの分化段階において正の制御因子として作用していること、さらにこの2つのシグナルは相乗的に作用する効果があることを明らかにした。
    2、ES細胞由来の膵幹細胞の解析
    時期特異的に成長増殖因子などを添加することで、ES細胞を消化管前駆細胞、膵臓前駆細胞のような特定の細胞系譜へ選択的に分化させることも可能になり、ES細胞由来の分化細胞をセルソーターを用いて純化し、その遺伝子発現プロファイルについて解析を行った。
    3、ES細胞由来の膵幹細胞の生体内分化能の解析-動物への移植による分化能の解析
    上記のES細胞由来の膵幹細胞の分化能について、生体内に移植し、生体内での生存、増殖、分化が可能かどうか、などの生体内における膵幹細胞の挙動、性質の変化について検討する。SCIDマウスの腎臓皮膜下に移植した場合、上記のPdx1陽性膵臓幹細胞からインスリン発現細胞への分化が観察された。したがって、ES細胞由来の膵臓幹細胞はインスリン発現細胞への分化能を有することが分った。

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  • 内胚葉系の発生・分化・再生の分子基盤

    Grant number：17637003  2005

    日本学術振興会  科学研究費助成事業  基盤研究(C)

    菊池 裕, 粂 昭苑, 福田 公子, 横内 裕二, 中越 英樹, 高橋 淑子

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    Grant amount：\3400000 （ Direct Cost: \3400000 ）

    本企画調査では,平成18年度に科学研究費補助金特定領域研究を組織するため、6名の研究代表者・分担者による研究会議・国内外の学会における情報収集・外国人研究者との意見交換を行った。
    1.研究会議;6・7・8・10月に、特定領域研究申請の為の研究打ち合わせを東京で行った。会議では、申請書の打ち合わせだけでなく内胚葉研究全般に関する情報交換や議論も行い、研究者同士の活発な議論が5〜6時間続けられた。
    2.学会における情報収集
    発生生物学会;6月、仙台、参加者(全員参加)
    国際発生生物学会;9月、オーストラリア・シドニー、参加者(菊池・粂)
    分子生物学会;12月、福岡、参加者(菊池・粂・横内・中越・高橋)
    発生生物における国内外の代表的な学会に参加し、内胚葉研究の現状と今後の方向性に関し、多くの国内外の研究者と活発な議論を行った。学会の参加により得られた様々な研究情報は、会議で報告し情報の共有化を行った。
    3.特定領域研究の申請;平成18年度発足の特定領域研究に「消化器形成の分子基盤」として研究計画書を作成し申請を行った。申請では、4つの研究項目(変異体作製・解析、基本デザイン・多様性、器官形成・細胞分化、再構築系)を設け、総勢16人による研究計画を立案した。
    本企画調査で行われた4回の研究会議では、内胚葉研究に関する議論・意見交換が活発に行われ、極めて有益であった。今後はこの会議の話し合いで得られた研究の方向性や共同研究等の実現を目指した活動を続けて行く予定である。

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  • ES細胞の試験管内分化系を用いた膵臓の発生分化の分子機構の解明

    Grant number：16027239  2004 - 2005

    日本学術振興会  科学研究費助成事業  特定領域研究

    粂 昭苑

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    Grant amount：\6000000 （ Direct Cost: \6000000 ）

    我々は、ES細胞から膵幹細胞を分化誘導するためには正常発生と同様な過程を経ることが重要であると考え、膵幹細胞マーカーであるpdx1の発現を指標にしている。そのためには、分化誘導に必要なシグナル源の探索から始めた。その結果、マウスES細胞を膵臓へ分化誘導するためには、マウス胎児膵臓原基との共培養が有効であることをこれまでに見出している(Shiraki et al. 2005)。しかしながら、胎児由来の組織はその性質上、誘導源として大量な材料を手に入れるのは困難である。そのため、胎児膵臓原基の代替となる誘導活性のある細胞を探索する必要がある。
    一方、自然な発生過程において、内胚葉の細胞が領域特異性を獲得するためには、中胚葉からのシグナルを必要とする現象が報告されている(Wells and Melton,2001)。様々な検討の結果、膵臓原基の代替となる誘導活性の高い培養細胞株を支持細胞として用いる方法を確立した。この方法では、外胚葉および中胚葉の細胞は分化誘導されずに、内胚葉の細胞が特異的に効率よく誘導されている。膵前駆細胞であるPdx1陽性細胞が10%程度誘導された。また、分化誘導後4日目には内胚葉マーカーであるFoxA2が80%のコロニーで検出されることより、この分化誘導の方法によって得られる分化細胞は内胚葉系譜の細胞が大きな割合を占めていると考えられた。
    更にpdx-1/GFPマウスからES細胞を樹立し、上記の分化誘導法と組み合わせることにより、各種因子が膵前駆細胞への分化に与える影響について経時的かつ簡便に観察することが可能となった。我々が開発した分化方法は、ES細胞から内胚葉を選択的かつ簡便に分化誘導できる全く新しい方法である。これまで十分な分化誘導方法がなく研究が困難であったES細胞から内胚葉由来臓器への分化を研究する上で強力な手法となると考える。

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  • ES細胞からの内胚葉細胞系譜制御遺伝子プロファイリング解析

    Grant number：16011248  2004

    日本学術振興会  科学研究費助成事業  特定領域研究

    粂 昭苑

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    Grant amount：\6500000 （ Direct Cost: \6500000 ）

    我々は、膵への発生分化の機序を明らかにするために、ES細胞を用いて、膵臓への分化過程を再現出来る実験系を構築している。これまでに、pdx1遺伝子座にlacZレポーター遺伝子をノックインしたES細胞を用いてきた。その結果、(i)膵臓原基とES細胞との共培養、(ii)TGF-・2の添加、(iii)ES細胞への内胚葉誘導因子c-mix遺伝子の強制発現、によってES細胞から膵への分化誘導が促進されることを明らかにした。
    さらに、ES細胞由来の膵幹細胞をリアルタイムで追跡し、生きた細胞を純化するために、pdx-1遺伝子の発現をGFP(緑色蛍光タンパク質)で可視化した。まず、GFPが膵臓幹細胞で特異的に発現されることがすでに確認されているpdx-1-GFPトランスジェニックマウス(Gu et al.,2002)より、ES細胞株を樹立した。このES細胞株から、効率よくES細胞から膵へ分化が誘導されることが確認された。ES細胞から誘導されたpdx-1/GFP陽性細胞をセルソーターを用いて、GFP陽性細胞の蛍光強度に基づき分画した。RT-PCR法により解析した結果、GFP陽性分画にpdx-1陽性細胞が濃縮されていることが分かった。このES細胞由来のpdx-1陽性細胞について、遺伝子発現網羅的解析を行なった。我々の系で得られた膵幹細胞の遺伝子プロファイルと、既に報告されているマウス胎生7.5日目の正常内胚葉層及び膵幹細胞の遺伝子発現プロファイル(Gu et al.,2003)と比較した結果、マウス胎生7.5日目の内胚葉で発現する遺伝子プロファイルとよく似ているプロファイルであることが明かとなった。従って、このES細胞の試験管内分化誘導の系を用いて正常発生を再現することができた。今後さらに異なるステージの内胚葉細胞系譜を純化し、その遺伝子網羅的発現解析を行なうことが期待できる。

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  • ES細胞から内胚葉系幹細胞への分化制御

    Grant number：15039226  2003 - 2004

    日本学術振興会  科学研究費助成事業  特定領域研究

    粂 昭苑, 粂 和彦

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    Grant amount：\5000000 （ Direct Cost: \5000000 ）

    我々は、膵への発生分化の機序を明らかにするために、ES細胞を用いて、膵臓への分化過程を再現出来る実験系を構築している。これまでに、膵幹細胞のマーカーであるpdx-1遺伝子発現を容易に検出可能のために、pdx1遺伝子座にlacZレポーター遺伝子をノックインしたES細胞を用いてきた。その結果、(i)膵臓原基とEs細胞との共培養、(ii)TGF-β2の添加、(iii)Es細胞への内胚葉誘導因子c-mix遺伝子の強制発現、によっでES細胞から膵への分化誘導が促進されることを明らかにした。
    さらに、ES細胞由来の膵幹細胞をリアルタイムで追跡し、生きた細胞を純化するために、pdx-1遺伝子の発現をGFP(緑色蛍光タンパク質)で可視化した。まず、pdx-1-GFPトランスジェニックマウス(Gu et al.,2002)より、ES細胞株を樹立した。トランスジェニックマウスにおいては、pdx-1遺伝子が膵臓幹細胞で特異的に発現されることがすでに確認されているので、樹立したES細胞から分化したGFP陽性細胞は膵に特異性があると考えられた。このES細胞株から、効率よくES細胞から膵へ分化が誘導されることが確認された。ES細胞から誘導されたpdx-1/GFP陽性細胞をセルソーターを用いて、GFP陽性細胞の蛍光強度に基づき分画した。RT-PCR法により解析した結果、GFP陽性分画にpdx-1陽性細胞が濃縮されていることが分かった。このES細胞由来のpdx-1陽性細胞について、遺伝子発現網羅的解析を行なった。我々の系で得られた膵幹細胞の遺伝子プロファイルと、既に報告されているマウス胎生7.5日目の正常内胚葉層及び膵幹細胞の遺伝子発現プロファイル(Gu et al.,2003)と比較した結果、マウス胎生7.5日目の内胚葉で発現する遺伝子プロファイルとよく似ているプロファイルであることが明らかとなった。

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  • Molecular Analysis of the sleep and arousal regulations and their relationship to the circadian rhythm using fruit fly, Drosophila melanogaster.

    Grant number：15300108  2003 - 2004

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (B)

    KUME Kazuhiko, KUME Shoen

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    Grant amount：\13500000 （ Direct Cost: \13500000 ）

    Physiologically, sleep is defined by electroencephalography, and typical REM and NREM sleep occur only in mammalian and avian species. But sleep-like inactive states also appear in other vertebrates and even in invertebrates. Similar to mammalian sleep, the inactive 'rest' state of insect is regulated by both circadian and homeostatic processes, which were demonstrated first in the cockroach 1, then in the fruit fly, Drosophila melanogaster. However, the similarity is based primarily on behavioral criteria.
    In the course of analyzing the nature of sleep-like rest behavior in Drosophila, we discovered by serendipity hyperactive sleepless mutant flies and named them fumin (fmn), which means 'sleepless' in Japanese. We then determined the nature of the mutation by forward genetics. To our surprise, we found that their behavioral phenotype is due to a genetic lesion in the dopamine transporter (DAT) gene. The elimination of DAT activity generates a continuous wakefulness in mutant flies, resulting in dramatically increased activity levels. finn mutants are more sensitive to mechanical stimuli when they are in prolonged immobility, indicating their decreased arousal threshold. They also show attenuations in rest (sleep) rebound.
    Mammalian DAT is a well-known target of psychostimulants, such as amphetamine and cocaine, and involved in wakefulness regulations. These results indicate a critical role of dopamine for arousal state in Drosophila and highlight a similarity between insects and mammals regarding the molecular basis of arousal. The use of a Drosophila model is expected to facilitate an understanding of arousal regulations.

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  • ES細胞からの内胚葉細胞系譜制御遺伝子プロファイリング解析

    Grant number：15011246  2003

    日本学術振興会  科学研究費助成事業  特定領域研究

    粂 昭苑, 粂 和彦

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    Grant amount：\6000000 （ Direct Cost: \6000000 ）

    申請者らが構築したES細胞から膵への分化誘導系において、アフリカツメガエルのmixファミリーのニワトリホモログであるc-mix遺伝子を強制発現させた結果、膵への分化誘導能が促進されたことを見い出している。このc-mix遺伝子強制発現ES細胞株と、対照株との遺伝子発現プロファイリング解析を行い、内胚葉誘導に関与する遺伝子群の同定出来ると考えられた。本研究ではDNAチップを用いた遺伝子解析を行なうと共に、rt-pcr法により、遺伝子導入株では内胚葉分化マーカーの発現が上昇していることを示した。今後はここで絞られた候補について、さらにアフリカツメガエル初期胚で強制発現させ、内胚葉誘導活性についてスクリーニングを続ける予定である。
    さらに、pdx-1-GFPトランスジェニックマウスより、ES細胞を樹立し、生きた状態でpdx-1の遺伝子発現を追跡可能の系を確立した。また、申請者らはこれまでに、ES細胞からの膵への分化誘導を支持する細胞を複数同定してきた。これら支持細胞を用いて、ES細胞から膵へ効率良く分化誘導された。さらに、ES細胞からの分化誘導の条件を無血清条件でアッセイできる系を確立し、TGFβ2を添加することにより、顕著な膵分化誘導を認めた。このように、これまでに確立した実験系では、充分に効率よくES細胞から膵へ分化を誘導することができたので、ES由来の膵幹細胞を今後セルソーターを用いて純化し、遺伝子発現プロファイリングなどによる細胞生化学的解析を進めようと考えている。

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