Small compounds promote differentiation of functional insulin producing cells

• Project/Area Number: 24790949
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Endocrinology
• Research Institution: Kumamoto University
• Principal Investigator: SAKANO Daisuke 熊本大学, 発生医学研究所, 助教 (40571039)
• Project Period (FY): 2012-04-01 – 2014-03-31
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2013: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2012: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
• Keywords: ES・iPS細胞 / 膵β細胞 / インスリン / 糖尿病 / 低分子化合物 / モノアミン / 膵臓 / β細胞 / VMAT2 / ｃAMP / ES・iPS / 膵 / ES / iPS

Research Abstract

Despite numerous efforts, it is still difficult to efficiently produce mature insulin-secreting beta cell from ES cells. Here, we focused on the late stages of the differentiation and performed a cell-based screening of chemical compound
library. We identified reserpine as a small molecule that inhibits vesicular monoamine transporter 2 (VMAT2)-mediated secretion of monoamine that promoted differentiation of Pdx1-positive progenitors into insulin-expressing cells. Our analyses suggest that one of the VMAT2-controlled monoamines, dopamine, serotonin and histamine negatively regulates beta cell differentiation. Exogenous addition of a cell-permeable cAMP analogue dBu-cAMP canceled these inhibitory effects on beta cell differentiation and synergized with VMAT2 inhibition. The ES cell derived beta cells showed glucose-sensitive insulin secretion ability, and reversed hyperglycemia upon engraftment into AKITA diabetic mice.

Research Products

• [Journal Article] VMAT2 identified as a regulator of late-stage beta cell differentiation (2014)
  • 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: Nature Chem. Biol Volume: 10(2) Pages: 141-8
  • NAID: 40020189460
  • Peer Reviewed
• [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] VMAT2 identified as a regulator of late-stage β-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
  • Organizer: ISSCR 11th annual meeting
  • Place of Presentation: Boston, USA
• [Presentation] VMAT2 identified as a regulator of late-stage pancreatic 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, Kume S.
  • Organizer: ISSCR 11th Annual Meeting.
  • Place of Presentation: Boston Convention and Exhibition Center, Boston,USA
• [Presentation] Small compounds promote differentiation of functional insulin producing cells. (2013)
  • Author(s): Sakano, D, Shiraki, N, Kikawa, K, Kataoka,M, Nagura, T, Choi, S, Endo F, Kume, K, Uesugi, M and Kume, S.
  • Organizer: 第36回日本分子生物学会年会
  • Place of Presentation: 神戸国際会議場, 兵庫
  • Invited
• [Presentation] SCREENING OF SMALL COMPOUNDS TO PROMOTE DIFFERENTIATION OF MOUSE ES CELLS TO FUNCTIONAL PANCREATIC β CELLS. (2013)
  • Author(s): Sakano, D., Shiraki, N., Kikawa, K., Kataoka,M., Nagura, T., Choi, S., Endo F., Kume, K1, Uesugi, M. and Kume, S.
  • Organizer: ISSCR 11th Annual Meeting.
  • Place of Presentation: Boston・Boston Convention and Exhibition Center （USA)
• [Presentation] 化合物スクリーニングによる膵β細胞誘導法の効率化 (2013)
  • Author(s): 坂野大介、白木伸明、片岡正光、木川和英、遠藤文夫、粂和彦、上杉志成、粂昭苑
  • Organizer: 5拠点ミーティング
  • Place of Presentation: 兵庫・有馬ホテル向陽閣
• [Presentation] Small compounds promote differentiation from pancreatic progenitor to endocrine cells MBSJ (2012)
  • Author(s): Sakano D, Shiraki N, Kikawa K, Kataoka M, Nagura T, Choi S, Endo F, Kume K, Uesugi M and Kume S
  • Organizer: MBSJ
  • Place of Presentation: Fukuoka
• [Presentation] 低分子化合物スクリーニングによる膵前駆細胞から内分泌前駆細胞への分化促進 (2012)
  • Author(s): 坂野 大介、白木 伸明、木川 和英、片岡 正光、名倉 岳志、崔 成翼、遠藤 文夫、粂 和彦、上杉 志成、粂 昭苑
  • Organizer: 第35回日本分子生物学会年会
  • Place of Presentation: 福岡・福岡国際会議場
• [Presentation] Screening of low molecular compounds that promote differentiation of mouse ES cells to pancreatic β cells. (2012)
  • Author(s): 坂野大介、白木伸明、片岡正光、木川和英、遠藤文夫、粂和彦、上杉志成、粂昭苑
  • Organizer: 第45回日本発生生物学会・第64回日本細胞生物学会合同大会
  • Place of Presentation: 兵庫・神戸国際会議場、神戸商工会議所
• [Presentation] Screening of low molecular compounds that promote differentiation of mouse ES cells to pancreatic β cells. (2012)
  • Author(s): 1. Sakano, D., Shiraki, N., Kataoka M., Kikawa K., Endo F., M., Kume, K, Uesugi, M. and Kume, S.
  • Organizer: ISSCR 10th Annual Meeting.
  • Place of Presentation: 神奈川・パシフィコ横浜
• [Presentation] A neonatal mouse model of pancreatic beta-cell regeneration after destruction by streptozotocin (2012)
  • Author(s): 2. Kataoka M.,Kawamuro Y., Miki R., Sakano, D., Shiraki, N., Yoshida T.,Kume K. and Kume, S.
  • Organizer: ISSCR 10th Annual Meeting.
  • Place of Presentation: 神奈川・パシフィコ横浜
• [Presentation] A novel chemical screening system for understanding of pancreatic β-cell differentiation from mouse ES cells. (2012)
  • Author(s): 2. Sakano、 D.、 Shiraki、 N.、 Kataoka、 Kikawa K.、 Endo F.、 M.、 Kume、 K、 Uesugi、 M. and Kume、 S.
  • Organizer: 第10回幹細胞シンポジウム
  • Place of Presentation: 兵庫・淡路夢舞台国際会議場
• [Book] 『発生・分化・再生と代謝関連臓器」「多能性幹細胞から膵 β 細胞への分化」 『内分泌・糖尿病・代謝内科』24(5) (2013)
  • Author(s): 坂野大介・粂昭苑
  • Publisher: 科学評論社
• [Book] 内分泌・糖尿病・代謝内科 特集 発生・分化・再生と代謝関連臓器 多能性幹細胞から膵β 細胞への分化, 第35巻第2号 (2012)
  • Author(s): 2.坂野 大介, 白木 伸明, 粂 昭苑
• [Book] 内分泌・糖尿病・代謝内科 特集 発生・分化・再生と代謝関連臓器 多能性幹細胞から膵β細胞への分化、 (2012)
  • Author(s): 坂野 大介、白木 伸明、粂 昭苑、
  • Total Pages: 6
  • Publisher: 科学評論社
• [Remarks] ES 細胞から成体と同等の能力を持つ膵臓の細胞を作製~糖尿病の治療へ新たな光明~
  • URL: http://www.kumamoto-u.ac.jp/daigakujouhou/kouhou/pressrelease/2013_file/release131216.pdf#search='%E8%86%B5%CE%B2%E7%B4%B0%E8%83%9E%E3%81%AE%E5%88%86%E5%8C%96%E3%82%92+%E5%B0%8F%E8%83%9E%E4%BD%93'
• [Remarks] 膵β細胞の分化を小胞型モノアミントランスポーター VMAT2が制御することを発見
  • URL: http://www.imeg.kumamoto-u.ac.jp/newpress/np67.html
• [Remarks] ES細胞から成熟膵β細胞を作製~糖尿病の治療を目指して~
  • URL: http://www.kumamoto-u.ac.jp/whatsnew/seimei/20131216
• [Remarks] 膵β細胞の分化を小胞型モノアミントランスポーター VMAT2が制御することを発見
  • URL: http://www.imeg.kumamoto-u.ac.jp/newpress/np67.html
• [Remarks] ES細胞から成熟膵β細胞を作製～糖尿病の治療を目指して～
  • URL: http://www.kumamoto-u.ac.jp/whatsnew/seimei/20131216