Molecular mechanisms regulating the differentiation for pancreatic bud-like cells from human pluripotent stem cells

• Project/Area Number: 18K08510
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 54040:Metabolism and endocrinology-related
• Research Institution: Kyoto University
• Principal Investigator: TOYODA TARO 京都大学, iPS細胞研究所, 講師 (60593530)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2020: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: NKX6.1 / PDX1 / 膵臓 / iPS細胞 / ES細胞 / siRNA / 糖尿病 / 膵芽 / 発生 / 分化

Outline of Final Research Achievements

Pancreatic bud/epithelial cells (NKX6.1+ cells) are considered as pancreas-committed cells. In this study, we aimed to exhaustively search molecules which regulate the differentiation into NKX6.1+ cells from human iPS cells. We have developed the screening system with using siRNA libraries to knock-down target genes for the analysis. We identified novel target molecule candidates and clarified that one of the target molecules promotes the differentiation. The mechanism we identified in this study may be useful for both basic research and clinical application using pancreatic cells.

Academic Significance and Societal Importance of the Research Achievements

膵芽・膵上皮細胞（NKX6.1+細胞）は、発生過程において膵臓への分化が決定された細胞である。NKX6.1+細胞への分化誘導は多能性幹細胞からの膵細胞作製において要所となる。しかしながら、ヒト幹細胞から膵芽細胞への分化機序や、試験管内で高効率に作製する方法は確立されていない。本研究では、ヒトiPS細胞からNKX6.1+細胞への分化を調節する新規の分子を同定した。本研究で解明したヒト多能性幹細胞からのNKX6.1+細胞の分化の仕組みは、膵臓に関連した疾患の対策に向けた基礎研究や臨床応用に有用である。

Research Products

• [Journal Article] Combined Omics Approaches Reveal the Roles of Non-canonical WNT7B Signaling and YY1 in the Proliferation of Human Pancreatic Progenitor Cells (2020)
  • Author(s): Kimura Azuma、Toyoda Taro、Iwasaki Mio、Hirama Ryusuke、Osafune Kenji
  • Journal Title: Cell Chemical Biology Volume: 27 Issue: 12 Pages: 1561-1572.e7
  • DOI: 10.1016/j.chembiol.2020.08.018
  • NAID: 120006958089
  • Peer Reviewed
• [Journal Article] 膵臓再生の up to date (2020)
  • Author(s): 豊田太郎、畑野悠、長船健二
  • Journal Title: 腎臓内科 Volume: 12 Pages: 329-336
  • NAID: 40022357506
• [Journal Article] Efficient Generation of Pancreas/Duodenum Homeobox Protein 1⁺ Posterior Foregut/Pancreatic Progenitors from hPSCs in Adhesion Cultures (2019)
  • Author(s): Toyoda Taro、Kimura Azuma、Tanaka Hiromi、Osafune Kenji
  • Journal Title: Journal of Visualized Experiments Volume: 145 Issue: 145 Pages: 1-11
  • DOI: 10.3791/57641
  • Peer Reviewed
• [Journal Article] Current status and future perspective of regenerative medicine for the pancreas (2018)
  • Author(s): 美馬 淳志、豊田 太郎、長船 健二
  • Journal Title: Nippon Shokakibyo Gakkai Zasshi Volume: 115 Issue: 8 Pages: 681-690
  • DOI: 10.11405/nisshoshi.115.681
  • NAID: 130007432026
  • ISSN: 0446-6586, 1349-7693
  • Year and Date: 2018-08-10
  • Open Access
• [Presentation] 再生医療応用に向けたヒトES/iPS細胞由来膵前駆細胞の増殖機序の解明 (2021)
  • Author(s): 木村東、豊田太郎、岩崎未央、平間竜介、長船健二
  • Organizer: 第20回日本再生医療学会総会
• [Presentation] Pancreatic research with iPSC technology. (2018)
  • Author(s): Toyoda T
  • Organizer: The 2nd Technion-Kyoto Joint Symposium
• [Book] 糖尿病最新の治療2019-2021（そのうち「XV 2. 再生医療」） (2019)
  • Author(s): 木村東、豊田太郎、長船健二（編集：門脇 孝、荒木 栄一、綿田 裕孝
  • Total Pages: 348
  • Publisher: 南江堂
  • ISBN: 4524245561