2. Academic Validation
  3. PGC-1α promotes mitochondrial respiration and biogenesis during the differentiation of hiPSCs into cardiomyocytes

PGC-1α promotes mitochondrial respiration and biogenesis during the differentiation of hiPSCs into cardiomyocytes

  • Genes Dis. 2020 Dec 23;8(6):891-906. doi: 10.1016/j.gendis.2020.12.006.
Qin Zhou 1 2 3,  Hao Xu 4,  Liang Yan 1 2,  Liang Ye 1 2,  Xinyuan Zhang 1 2,  Bin Tan 1 2,  Qin Yi 1 2,  Jie Tian 5,  Jing Zhu 1 2
Affiliations

Affiliations

  • 1 Department of Pediatric Research Institute, Ministry of Education Key Laboratory of Child Development and Disorders National Clinical Research Center for Child Health and Disorders (Chongqing) China International Science and Technology Cooperation Base of Child Development and Critical Disorders Children's Hospital of Chongqing Medical University, Chongqing, 400000, PR China.
  • 2 Chongqing Key Laboratory of Pediatrics, Chongqing, 400000, PR China.
  • 3 Chengdu Women's and Children's Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan Province, 610073, PR China.
  • 4 Department of Clinical Laboratory Ministry of Education Key Laboratory of Child Development and Disorders National Clinical Research Center for Child Health and Disorders (Chongqing) China International Science and Technology Cooperation Base of Child Development and Critical Disorders Children's Hospital of Chongqing Medical University, Chongqing, 400000, PR China.
  • 5 Department of Cardiovascular (Internal Medicine), Ministry of Education Key Laboratory of Child Development and Disorders National Clinical Research Center for Child Health and Disorders (Chongqing) China International Science and Technology Cooperation Base of Child Development and Critical Disorders Children's Hospital of Chongqing Medical University, Chongqing, 400000, PR China.
PMID: 34522716 DOI: 10.1016/j.gendis.2020.12.006
Abstract

Although it is widely accepted that human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are readily available, robustly reproducible, and physiologically appropriate human cells for clinical applications and research in the cardiovascular field, hiPSC-CMs cultured in vitro retain an immature metabolic phenotype that limits their application, and little is known about the underlying molecular mechanism controlling mitochondrial metabolic maturation during human induced pluripotent stem cells (hiPSCs ) differentiation into cardiomyocytes. In this study, we found that Peroxisome Proliferator-activated Receptor γ coactivator-1α (PGC-1α) played an important role in inducing mitochondrial biogenesis and establishing Oxidative Phosphorylation (OXPHOS) during the cardiac differentiation of hiPSCs. Knocking down PGC-1α by siRNA impaired mitochondrial respiration, while upregulating PGC-1α by ZLN005 promoted mitochondrial biosynthesis and function by regulating the expression of downstream genes involved in mitochondrial dynamics and oxidative metabolism in hiPSC-CMs. Furthermore, we found that estrogen-related receptor α (ERRα) was required for the induction of PGC-1α stimulatory effects in hiPSC-CMs. These findings provide key insights into the molecular control of Mitochondrial Metabolism during cardiac differentiation and may be used to generate more metabolically mature cardiomyocytes for application.

Keywords

Cardiac differentiation; Maturation; Mitochondrial metabolism; PGC-1α; hiPSCs.

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