2. Academic Validation
  3. HIF-1α Affects the Neural Stem Cell Differentiation of Human Induced Pluripotent Stem Cells via MFN2-Mediated Wnt/β-Catenin Signaling

HIF-1α Affects the Neural Stem Cell Differentiation of Human Induced Pluripotent Stem Cells via MFN2-Mediated Wnt/β-Catenin Signaling

  • Front Cell Dev Biol. 2021 Jun 21;9:671704. doi: 10.3389/fcell.2021.671704.
Peng Cui 1,  Ping Zhang 2,  Lin Yuan 1 3,  Li Wang 4,  Xin Guo 5,  Guanghui Cui 5,  Yanmin Zhang 5,  Minghua Li 5,  Xiaowei Zhang 6,  Xiaoqiang Li 7,  Yuxin Yin 1 8,  Zhendong Yu 5
Affiliations

Affiliations

  • 1 Institute of Precision of Medicine, Peking University Shenzhen Hospital, Shenzhen, China.
  • 2 Department of Hematology, Peking University Shenzhen Hospital, Shenzhen, China.
  • 3 Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX, United States.
  • 4 Department of Oncology, Peking University Shenzhen Hospital, Shenzhen, China.
  • 5 Central Laboratory, Peking University Shenzhen Hospital, Shenzhen, China.
  • 6 School of Basic Medical Sciences, Peking University, Beijing, China.
  • 7 Department of Thoracic Surgery, Peking University Shenzhen Hospital, Shenzhen, China.
  • 8 Institute of Systems Biomedicine, Department of Pathology, School of Basic Medical Sciences, Peking-Tsinghua Center for Life Sciences, Peking University Health Science Center, Beijing, China.
PMID: 34235146 DOI: 10.3389/fcell.2021.671704
Abstract

Hypoxia-inducible factor 1α (HIF-1α) plays pivotal roles in maintaining pluripotency, and the developmental potential of pluripotent stem cells (PSCs). However, the mechanisms underlying HIF-1α regulation of neural stem cell (NSC) differentiation of human induced pluripotent stem cells (hiPSCs) remains unclear. In this study, we demonstrated that HIF-1α knockdown significantly inhibits the pluripotency and self-renewal potential of hiPSCs. We further uncovered that the disruption of HIF-1α promotes the NSC differentiation and development potential in vitro and in vivo. Mechanistically, HIF-1α knockdown significantly enhances mitofusin2 (MFN2)-mediated Wnt/β-catenin signaling, and excessive mitochondrial fusion could also promote the NSC differentiation potential of hiPSCs via activating the β-catenin signaling. Additionally, MFN2 significantly reverses the effects of HIF-1α overexpression on the NSC differentiation potential and β-catenin activity of hiPSCs. Furthermore, Wnt/β-catenin signaling inhibition could also reverse the effects of HIF-1α knockdown on the NSC differentiation potential of hiPSCs. This study provided a novel strategy for improving the directed differentiation efficiency of functional NSCs. These findings are important for the development of potential clinical interventions for neurological diseases caused by metabolic disorders.

Keywords

differentiation; hypoxia-inducible factor 1α; induced pluripotent stem cells; mitofusin2; neural stem cells.

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