Direct reprogramming of human fibroblasts into hematopoietic cells mainly using ETV2

• Project/Area Number: 26670470
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Hematology
• Research Institution: Keio University
• Principal Investigator: Morita Rimpei 慶應義塾大学, 医学部, 准教授 (00362541)
• Co-Investigator(Renkei-kenkyūsha): YOSHIMURA Akihiko 慶應義塾大学, 医学部, 教授 (90182815)
• Project Period (FY): 2014-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000); Fiscal Year 2015: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2014: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 造血幹細胞 / 転写因子 / エピジェネティクス / 血管内皮細胞 / リンパ球

Outline of Final Research Achievements

An ETS family transcription factor ETV2 is essential for hemato-endothelial development in embryo. We have reported that human adult skin fibroblasts directly convert into functional endothelial cells by transducing ETV2.
Interestingly we found that ETV2-transduced human adult skin fibroblasts also expressed RUNX1, TAL1, and GATA2, which were transcription factors essential for hematopoiesis. Thus to generate hematopoietic cells from fibroblasts, we transduced not only ETV2 but also 20 kinds of transcription factors essential for hematopoiesis into human adult skin fibroblasts, then co-cultured them with OP9 stroma cells in the presence of SCF, FLT3L, TPO, IL-3, and IL-6 for four weeks. Consequently we detected CD45+c-Kit+ hematopoietic-like cells by FACS analysis. Our results may leads to generation of functional hematopoietic cells from individual skin in the future.

Research Products

• [Journal Article] ETS transcription factor ETV2 directly converts human fibroblasts into functional endothelial cells. (2015)
  • Author(s): Morita R, Suzuki M, Kasahara H, Shimizu N, Shichita T, Sekiya T, Kimura A, Sasaki K, Yasukawa H, Yoshimura A.
  • Journal Title: Proc Natl Acad Sci U S A. Volume: 112 Issue: 1 Pages: 160-165
  • DOI: 10.1073/pnas.1413234112
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Suppression of Th2 and Tfh immune reactions by Nr4a receptors in mature T reg cells (2015)
  • Author(s): Sekiya T, Kondo T, Shichita T, Morita R, Ichinose H, Yoshimura A
  • Journal Title: J Exp Med. Volume: 212 Issue: 10 Pages: 1623-1640
  • DOI: 10.1084/jem.20142088
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Ｔ細胞の免疫リプログラミング (2016)
  • Author(s): 吉村昭彦、近藤泰介、染谷和江、岡田匡央、森田林平
  • Organizer: 第１５回日本再生医療学会総会
  • Place of Presentation: 大阪国際会議場 （大阪府大阪市）
  • Year and Date: 2016-03-17
  • Invited
• [Book] 細胞工学別冊 ダイレクトリプログラミング (2015)
  • Author(s): 森田林平、笠原秀範、吉村昭彦
  • Total Pages: 119
  • Publisher: 秀潤社
• [Book] 日本臨牀増刊号 再生医療 (2015)
  • Author(s): 森田林平、笠原秀範、吉村昭彦
  • Total Pages: 584
  • Publisher: 日本臨牀社
• [Book] ダイレクトリプログラミング （第3章 線維芽細胞→血管内皮細胞） (2015)
  • Author(s): 森田林平、笠原秀範、吉村昭彦
  • Total Pages: 11
  • Publisher: 秀潤社