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

• Project/Area Number: 26253059
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Metabolomics
• Research Institution: Tokyo Institute of Technology
• Principal Investigator: Kume Shoen 東京工業大学, 生命理工学院, 教授 (70347011)
• Co-Investigator(Kenkyū-buntansha): 荒木 喜美 熊本大学, 学内共同利用施設等, 教授 (90211705)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥41,340,000 (Direct Cost: ¥31,800,000、Indirect Cost: ¥9,540,000); Fiscal Year 2016: ¥12,740,000 (Direct Cost: ¥9,800,000、Indirect Cost: ¥2,940,000); Fiscal Year 2015: ¥13,520,000 (Direct Cost: ¥10,400,000、Indirect Cost: ¥3,120,000); Fiscal Year 2014: ¥15,080,000 (Direct Cost: ¥11,600,000、Indirect Cost: ¥3,480,000)
• Keywords: 多能性幹細胞 / 分化誘導 / 糖尿病 / 再生医療 / 膵臓 / 代謝 / 増殖 / モノアミン / ドパミン / インスリン / 化合物 / 再生医学 / 膵β細胞 / 膵臓β細胞

Outline of Final Research Achievements

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.

Research Products

• [Journal Article] Heterogeneity of beta-cells. (2017)
  • Author(s): Shoen Kume
  • Journal Title: J Diabetes Investig Volume: 印刷中 Issue: 5 Pages: 656-657
  • DOI: 10.1111/jdi.12608
  • Peer Reviewed / Open Access
• [Journal Article] Changes in expression of C2cd4c in pancreatic endocrine cells during pancreatic development (2016)
  • Author(s): Omori H, Ogaki S, Sakano D, Sato M, Umeda K, , Nakagata N, Kume S
  • Journal Title: FEBS Lett Volume: 590 Issue: 16 Pages: 2584-93
  • DOI: 10.1002/1873-3468.12271
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Dopamine D2 receptor-mediated regulation of pancreatic b cell mass. (2016)
  • Author(s): １.Sakano D, Choi S, Kataoka M, Shiraki N, Uesugi M, Kume K, Kume S
  • Journal Title: Stem Cell Reports Volume: ７ Issue: 1 Pages: 95-109
  • DOI: 10.1016/j.stemcr.2016.05.015
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Late stage definitive endodermal differentiation can be defined by Daf1 expression (2016)
  • Author(s): Ogaki S, Omori H, Morooka M, Shiraki N, Ishida S, Kume S
  • Journal Title: BMC Dev Biol Volume: 16 Issue: 1 Pages: 19-19
  • DOI: 10.1186/s12861-016-0120-2
  • Peer Reviewed / Open Access
• [Journal Article] Quantification of intracellular Zn, Fe, Cu within both iPS cells and differentiated cells using HPLC coupled to ICP-MS. (2016)
  • Author(s): Arakawa A, Shiraki N, Tsuyama T, Kume S, Iwahata D, Yamada N
  • Journal Title: J. Anal Bioanal Tech Volume: 7 Pages: 1000295-1000295
  • Peer Reviewed
• [Journal Article] Temporal effects of Notch signaling and potential cooperation with multiple downstream effectors on adenohypophysis cell specification in zebrafish (2016)
  • Author(s): Y. Nakahara, A. Muto, R. Hirabayashi, T. Sakuma, T. Yamamoto, S. Kume, and Y. Kikuchi
  • Journal Title: Genes to Cells Volume: 21 Issue: 5 Pages: 492-504
  • DOI: 10.1111/gtc.12358
  • Peer Reviewed
• [Journal Article] Neural cells play an inhibitory role in pancreatic differentiation of pluripotent stem cells. (2015)
  • Author(s): Nakashima R, Morooka M, Shiraki N, Sakano D, Ogaki S, Kume K, Kume S
  • Journal Title: Genes to cells Volume: 20 Issue: 12 Pages: 1028-45
  • DOI: 10.1111/gtc.12308
  • Peer Reviewed / Open Access
• [Journal Article] The NMDA receptor promotes sleep in the fruit fly, Drosophila melanogaster. (2015)
  • Author(s): Tomita, J., Ueno, T., Mitsuyoshi, M., Kume, S. and Kume, K.
  • Journal Title: PLoS ONE Volume: 10 Issue: 5 Pages: e0128101-e0128101
  • DOI: 10.1371/journal.pone.0128101
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] A cost effective system for differentiation of intestinal epithelium from human induced pluripotent stem cells. (2015)
  • Author(s): Ogaki S, Morooka M, Otera K and Kume S.
  • Journal Title: Sci Rep Volume: 5 Issue: 1 Pages: 17297-17297
  • DOI: 10.1038/srep17297
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Methionine metabolism regulates maintenance and differentiation of human pluripotent stem cells. (2014)
  • Author(s): Shiraki, N., Shiraki, Y., Tsuyama, T., Obata, F., Miura, M., Nagae, G., Aburatani, H., Kume, K., Endo, F., and Kume, S.
  • Journal Title: Cell Metab. Volume: 19 Issue: 5 Pages: 780-794
  • DOI: 10.1016/j.cmet.2014.03.017
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] High Oxygen Condition Facilitates the Differentiation of Mouse and Human Pluripotent Stem Cells into Pancreatic Progenitors and Insulin-producing Cells. (2014)
  • Author(s): Farzana Hakim, Taku Kaitsuka, Jamiruddin Mohd. Raeed, Fan-Yan Wei, Nobuaki Shiraki, Tadayuki Akagi, Takashi Yokota, Shoen Kume, and Kazuhito Tomizawa
  • Journal Title: The journal of biological chemistry Volume: 289 Issue: 14 Pages: 9623-9638
  • DOI: 10.1074/jbc.m113.524363
  • Peer Reviewed / Open Access
• [Journal Article] Beneficial effect of insulin treatment on islet transplantation outcomes in akita mice. (2014)
  • Author(s): Kikawa K, Sakano D, Shiraki N, Tsuyama T, Kume K, Endo F, Kume S.
  • Journal Title: Plos one Volume: 9(4) Issue: 4 Pages: e95451-e95451
  • DOI: 10.1371/journal.pone.0095451
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Profiling of embryonic stem cell differentiation. (2014)
  • Author(s): Shiraki N., Ogaki S and Kume S
  • Journal Title: The Review of Diabetic Studies Volume: 11(1) Issue: 1 Pages: 102-114
  • DOI: 10.1900/rds.2014.11.102
  • Peer Reviewed
• [Journal Article] Generation of insulin-producing beta-like cells from human iPS cells in a defined and completely Xeno-free culture system. (2014)
  • Author(s): Shahjalal HM, Shiraki N, Sakano D, Kikawa H, Ogaki S, Baba H, Kume K., Kume S.
  • Journal Title: Journal of Molecular Cell Biology Volume: 6 Issue: 5 Pages: 394-408
  • DOI: 10.1093/jmcb/mju029
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] VMAT2 identified as a regulator of late-stage beta cell differentiation. (2013)
  • Author(s): Sakano, D., Shiraki, N., Kikawa, K., Yamazoe, T., Kataoka, M., Umeda, K., Araki, K., Mao, D., Matsumoto, S., Nakagata, N., Andersson, O., Stainier, D., Endo, F., Kume, K., Uesugi, M. and Kume, S.
  • Journal Title: Nat. Chem. Biol. Volume: 10 Issue: 2 Pages: 141-148
  • DOI: 10.1038/nchembio.1410
  • Peer Reviewed
• [Presentation] ヒトiPS細胞におけるメチオニン代謝とヒストン修飾の役割の解明 (2016)
  • Author(s): 神戸梓沙、白木伸明、木村宏、粂昭苑
  • Organizer: 分子生物学会
  • Place of Presentation: 横浜市
  • Year and Date: 2016-11-30
• [Presentation] モノアミンによるインスリン分泌制御機構の解明 (2016)
  • Author(s): 上船史弥、園田雄輝、坂野大介、粂昭苑
  • Organizer: 分子生物学会
  • Place of Presentation: 横浜市
  • Year and Date: 2016-11-30
• [Presentation] Generation of insulin-producing β-like cells from human iPS cell (2016)
  • Author(s): Shoen Kume
  • Organizer: 11th IDF WPR & 8th AASD meeting
  • Place of Presentation: Taipei
  • Year and Date: 2016-10-28
  • Int'l Joint Research / Invited
• [Presentation] Monoamine signaling controls cell proliferation and differentiation state of pancreatic beta cell (2016)
  • Author(s): Daisuke Sakano, Choi Sungik, Masateru Kataoka, Nobuaki Shiraki, Shoen Kum
  • Organizer: 日本生化学会
  • Place of Presentation: 仙台
  • Year and Date: 2016-09-25
• [Presentation] 多能性幹細胞の分化制御と代謝 (2016)
  • Author(s): 粂昭苑
  • Organizer: 細胞生物学会
  • Place of Presentation: 京都
  • Year and Date: 2016-06-15
  • Invited
• [Presentation] Monoamine signals that control differentiation and proliferation of pancreatic beta cells. (2016)
  • Author(s): Shoen Kume
  • Organizer: CDB symposium
  • Place of Presentation: 神戸
  • Year and Date: 2016-03-28
• [Presentation] ヒトiPS細胞由来膵臓細胞を用いた膵臓β細胞分化を促進する化合物の探索 (2016)
  • Author(s): 白木伸明、師岡茉由 、白濱理絵 、山下智大、粂昭苑
  • Organizer: 日本薬学会135年会
  • Place of Presentation: 神戸
  • Year and Date: 2016-03-26
  • Invited
• [Presentation] ヒトES/iPS細胞の未分化能維持と分化 におけるメチオニン代謝 (2016)
  • Author(s): 白木伸明 粂 昭苑
  • Organizer: 第15回日本再生医療学会総会
  • Place of Presentation: 横浜
  • Year and Date: 2016-03-19
  • Invited
• [Presentation] 多能性幹細胞から膵β細胞への分化誘導 (2016)
  • Author(s): 粂昭苑
  • Organizer: 第15回日本再生医療学会総会
  • Place of Presentation: 大阪
  • Year and Date: 2016-03-17
  • Invited
• [Presentation] 多能性幹細胞を用いた糖尿病の再生治療のアプローチ (2016)
  • Author(s): 粂昭苑
  • Organizer: 第43回日本膵・膵島移植研究会
  • Place of Presentation: 広島市
  • Year and Date: 2016-03-04
  • Invited
• [Presentation] 多能性幹細胞を用いた糖尿病の再生・創薬研究 (2016)
  • Author(s): 粂昭苑
  • Organizer: 国立国際医療研究センター 研究所セミナー
  • Place of Presentation: 東京
  • Year and Date: 2016-02-22
  • Invited
• [Presentation] 多能性幹細胞を使った消化器官の再生医療への取組み (2016)
  • Author(s): 粂昭苑
  • Organizer: 第19回再生医療の実用化に関するニーズ発表会
  • Place of Presentation: 神戸
  • Year and Date: 2016-02-12
  • Invited
• [Presentation] 多能性幹細胞を用いた膵β細胞の再生医療への展望 (2016)
  • Author(s): 粂昭苑
  • Organizer: 千葉次世代糖尿病治療研究会
  • Place of Presentation: 千葉市
  • Year and Date: 2016-01-14
  • Invited
• [Presentation] Pluripotent stem cells for modeling cellular biology, developmental biology and regenerative medicine (2016)
  • Author(s): Shoen Kume
  • Organizer: 第4回の生命理工国際シンポジウム
  • Place of Presentation: 横浜
  • Year and Date: 2016-01-13
• [Presentation] 多能性幹細胞から膵臓β細胞を創る (2016)
  • Author(s): 粂 昭苑
  • Organizer: 「細胞を創る」研究会9.0
  • Place of Presentation: 東京
  • Invited
• [Presentation] Generation of insulin-producing β-like cells from human iPS cells (2016)
  • Author(s): Shoen Kume
  • Organizer: 10th International Conference on Cell Therapy (IRICT)
  • Place of Presentation: Seoul
  • Int'l Joint Research / Invited
• [Presentation] 幹細胞の未分化維持及び分化におけるメチオニン代謝の役割 (2016)
  • Author(s): 門馬 紗英子、白木伸明、及川彰、粂昭苑
  • Organizer: 細胞生物学会
  • Place of Presentation: 京都
• [Presentation] 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 (2015)
  • Author(s): 粂昭苑
  • Organizer: BMB2015
  • Place of Presentation: 横浜
  • Year and Date: 2015-12-02
• [Presentation] 膵β細胞の複製を促進する低分子化合物の探索 (2015)
  • Author(s): 坂野大介・崔 成翼・片岡正光・粂昭苑
  • Organizer: BMB2015
  • Place of Presentation: 横浜
  • Year and Date: 2015-12-02
• [Presentation] ES/iPS細胞を用いた糖尿病の創薬研究 (2015)
  • Author(s): 粂昭苑
  • Organizer: Bio Japan
  • Place of Presentation: 横浜
  • Year and Date: 2015-10-15
• [Presentation] 多能性幹細胞を用いた膵β細胞の再生治療 (2015)
  • Author(s): 粂昭苑
  • Organizer: 第15回Islet Biology 研究会
  • Place of Presentation: 東京都
  • Year and Date: 2015-07-17
  • Invited
• [Presentation] 多能性幹細胞を応用した膵β細胞の再生治療 (2015)
  • Author(s): 粂昭苑
  • Organizer: 第67回 糖尿病血管障害講演会
  • Place of Presentation: 東京都
  • Year and Date: 2015-06-17
  • Invited
• [Presentation] 多能性幹細胞を用いた肝と膵の再生医学研究 (2015)
  • Author(s): 粂昭苑
  • Organizer: 第22回肝細胞研究会
  • Place of Presentation: 米子
  • Year and Date: 2015-06-04
  • Invited
• [Presentation] 膵β細胞の複製を促進する低分子化合物の探索 (2014)
  • Author(s): 坂野大介、崔 成翼、片岡正光、粂昭苑
  • Organizer: 第37回日本分子生物学会
  • Place of Presentation: 横浜
  • Year and Date: 2014-11-26
• [Presentation] ヒト多能性幹細胞の未分化維持および分化におけるメチオニン代謝の役割 (2014)
  • Author(s): 白木 伸明, 白木 恭子, 津山 友徳, 小幡 史明, 三浦 正幸, 永江 玄太, 油谷 浩幸, 粂 和彦, 遠藤 文夫, 粂 昭苑
  • Organizer: 第37回日本分子生物学会
  • Place of Presentation: 横浜
  • Year and Date: 2014-11-26
• [Presentation] Signals that control differentiation of ES/iPS cells into pancreatic beta cells (2014)
  • Author(s): Shoen Kume
  • Organizer: The 8th International Conference on Cell Therapy
  • Place of Presentation: Seoul
  • Year and Date: 2014-10-23
  • Int'l Joint Research / Invited
• [Presentation] 多能性幹細胞モデルを用いた膵臓の発生分化研究 (2014)
  • Author(s): 粂 昭苑
  • Organizer: 第87回日本生化学会大会
  • Place of Presentation: 京都
  • Year and Date: 2014-10-16
  • Invited
• [Presentation] iPS技術を用いた膵β細胞の分化誘導研究 (2014)
  • Author(s): 粂 昭苑
  • Organizer: 第29回日本糖尿病合併症学会
  • Place of Presentation: 東京都
  • Year and Date: 2014-10-04
  • Invited
• [Presentation] Methionine metabolism regulates maintenance and differentiation of human pluripotent stem cells (2014)
  • Author(s): Nobuaki Shiraki and Shoen Kume
  • Organizer: Key Forum: From Stem Cells to Organs
  • Place of Presentation: Kumamoto
  • Year and Date: 2014-09-04
  • Int'l Joint Research / Invited
• [Presentation] Chemical genetic identification of signals that control late-stage pancreatic beta cell differentiation (2014)
  • Author(s): Shoen Kume
  • Organizer: ISSCR (International Society of Stem Cell Research)
  • Place of Presentation: Vancouber
  • Year and Date: 2014-06-20
  • Int'l Joint Research
• [Presentation] Signals that control differentiation of pluripotent stem cells into pancreatic beta cells (2014)
  • Author(s): Shoen Kume
  • Organizer: Tissue Engineering Regenerative Medicine International Society (TERMIS-EU 2014)
  • Place of Presentation: Genova
  • Year and Date: 2014-06-10
  • Int'l Joint Research / Invited
• [Presentation] 再生医療を用いた糖尿病治療の今後の展望 (2014)
  • Author(s): 粂昭苑
  • Organizer: 日本内分泌学会学術総会
  • Place of Presentation: 福岡
  • Year and Date: 2014-04-25
  • Invited
• [Book] 新膵臓病学 第2章膵の発生 (2017)
  • Author(s): 粂 昭苑
  • Publisher: 南江堂
• [Remarks] 研究成果概要 粂・白木研究室
  • URL: http://www.stem.bio.titech.ac.jp/results.html
• [Remarks] 東京工業大学 生命理工学系 News
  • URL: http://educ.titech.ac.jp/bio/news/2016_07/052422.html
• [Remarks] 研究室ウエブページの研究紹介
  • URL: http://www.stem.bio.titech.ac.jp/results.html
• [Patent(Industrial Property Rights)] インスリン産生細胞の分化誘導方法 (2015)
  • Inventor(s): 粂 昭苑、白木伸明
  • Industrial Property Rights Holder: 粂 昭苑、白木伸明
  • Industrial Property Rights Type: 特許
  • Filing Date: 2015-05-19
  • Overseas
• [Patent(Industrial Property Rights)] アミノ酸組成変更培地を用いた幹細胞の分化促進方法、及び該方法を用いて処理された幹細胞、並びに培地 (2015)
  • Inventor(s): 粂 昭苑、遠藤文夫、白木伸明、白木恭子、粂 和彦、馬渡一徳
  • Industrial Property Rights Holder: 粂 昭苑、遠藤文夫、白木伸明、白木恭子、粂 和彦、馬渡一徳
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2014-184294
  • Filing Date: 2015-09-10
• [Patent(Industrial Property Rights)] インスリン産生細胞の分化誘導方法 (2014)
  • Inventor(s): 粂 昭苑、白木伸明
  • Industrial Property Rights Holder: 粂 昭苑、白木伸明
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2014-104019
  • Filing Date: 2014-05-20