Improved hematopoietic differentiation of primate embryonic stem cells by inhibition of the PI3K-AKT pathway under defined conditions

Takenobu Nii, Tomotoshi Marumoto, Hiroshi Kohara, Saori Yamaguchi, Hirotaka Kawano, Erika Sasaki, Yoshie Kametani, Kenzaburo Tani

研究成果: Contribution to journalArticle査読

6 被引用数 (Scopus)

抄録

Hematopoietic stem/progenitor cells (HSPCs) derived from embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) have potential therapeutic applications in humans. To assess the safety and efficacy of ESC/iPSC-based therapies, reliable animal models are required prior to their clinical application. The common marmoset (CM) was recently found to be a useful nonhuman primate animal model for drug development and safety assessment. However, a method for the efficient hematopoietic differentiation of CM ESCs has not been established. In this study, we developed a novel and efficient method for differentiating CM ESCs into hematopoietic cells by transiently inhibiting the phosphoinositide 3-kinase (PI3K)-Protein kinase B (AKT) pathway, a critical pathway that maintains the undifferentiated state of CM ESCs during embryoid body (EB) formation. Compared with controls, transient inhibition of the P13K-AKT pathway resulted in a threefold increase in the proportion of enriched CD34+ cells (p < 0.001) and an increase in the number of hematopoietic colonies on day 8 of CM EB cultures. Moreover, number of blast colonies, number of hematopoietic progenitor cell populations of CD34+CD117+, CD34+CD45+, and CD43+CD45+ cells, and expression of hematopoietic genes were increased by transient inhibition of the PI3K-AKT pathway. We also demonstrated that the hematopoietic progenitor cell population was increased by inhibition of PI3K in a human system. Our novel and efficient ESC differentiation method might be useful for preclinical research on human hematopoietic disorders and may be efficiently translated to human ESC/iPSC-based regenerative medicine.

本文言語英語
ページ(範囲)901-911.e4
ジャーナルExperimental Hematology
43
10
DOI
出版ステータス出版済み - 10 1 2015

All Science Journal Classification (ASJC) codes

  • 分子生物学
  • 血液学
  • 遺伝学
  • 細胞生物学
  • 癌研究

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