Induction of Mesenchymal Stem Cells from Somatic Cells by Direct Reprograming/Transdifferentiaition

• Project/Area Number: 26861217
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Orthopaedic surgery
• Research Institution: Kindai University
• Principal Investigator: TERAMURA Takeshi 近畿大学, 医学部附属病院, 講師 (40460901)
• Research Collaborator: ASAHARA Hiroshi 東京医科歯科大学, 医学部, 教授 ; Lotz Martin スクリプス研究所, 分子実験医学部門, 教授
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000); Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2015: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000); Fiscal Year 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 再生医療 / 間葉系幹細胞 / リプログラミング / ダイレクトリプログラミング / 上皮間葉転換 / 転写因子 / Twist1 / TGFβシグナル / iPS細胞

Outline of Final Research Achievements

Mesenchymal stem cells (MSCs) are multipotent stem cells that are present in multiple tissues. Recent studies demonstrated that MSCs can support wound healing and tissue regeneration. On the other hand, adult MSCs exhibit cellular senescence during ex vivo expansion, which is accompanied by a reduction in self-renewal and multidifferentiation potential. To resolve this, identification of master molecules and central cascades involving MSC self-renewal is essential. Here, we focused on Twist1, which is a master regulator of epithelial-mesenchymal transition (EMT), and examined it’s roles in MSCs. Suppression of Twist1 leaded to reduction of Sox2, Bmi1, and Gata6 expressions. Contrary, over-expression of Twist1 induced expression of these genes. Mass spectrometric analysis showed that Tiwist1 involves epigenetic modification. Finally, we demonstrated that direct induction of MSCs from human monocytes was possible by introduce Twist1 with reprogramming factors.

Research Products

• [Journal Article] TWIST1 induces MMP3 expression through up-regulating DNA hydroxymethylation and promotes catabolic responses in human chondrocytes. (2017)
  • Author(s): Hasei J, Teramura T, Takehara T, Onodera Y, Horii T, Olmer M, Hatada I, Fukuda K, Ozaki T, Lotz M, Asahara H*.
  • Journal Title: Sci Rep. Volume: ７ Issue: 1 Pages: 42990-42990
  • DOI: 10.1038/srep42990
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Inflammation-induced miRNA-155 inhibits self-renewal of neural stem cells via suppression of CCAAT/enhancer binding protein β (C/EBPβ) expression (2017)
  • Author(s): Obora K, Onodera Y, Takehara T, Frampton J, Hasei J, Ozaki T, Teramura T, Fukuda K
  • Journal Title: Scientific Reports Volume: 7 Issue: 1 Pages: 43604-43604
  • DOI: 10.1038/srep43604
  • Peer Reviewed / Open Access
• [Journal Article] Cdh2 stabilizes FGFR1 and contributes to primed-state pluripotency in mouse epiblast stem cells (2015)
  • Author(s): Toshiyuki Takehara
  • Journal Title: Scientific Reports Volume: 5 Issue: 1 Pages: 14722-14722
  • DOI: 10.1038/srep14722
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Gene-modified embryonic stem cell test to characterize chemical risks. (2015)
  • Author(s): Kitada K, Kizu A, Teramura T, Takehara T, Hayashi M, Tachibana D, Wanibuchi H, Fukushima S, Koyama M, Yoshida K, Morita T.
  • Journal Title: Environ Sci Pollut Res Int. Volume: 22 Issue: 22 Pages: 18252-18259
  • DOI: 10.1007/s11356-015-5051-0
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] 多能性幹細胞からの間葉系幹細胞の分化誘導と軟骨再生 (2016)
  • Author(s): 寺村岳士、浅原弘嗣、福田寛二
  • Organizer: 日本整形外科学会基礎学術集会
  • Place of Presentation: 福岡国際会議場(福岡県）
  • Year and Date: 2016-10-13
  • Invited