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Research Paper|Volume 12, Issue 8|pp 7411—7430

PGC-1α activator ZLN005 promotes maturation of cardiomyocytes derived from human embryonic stem cells

Yanping Liu1, Huajun Bai2, Fengfeng Guo3,4, Phung N. Thai5, Xiaoling Luo2, Peng Zhang2, Chunli Yang1, Xueqin Feng1, Dan Zhu1, Jun Guo1, Ping Liang3,4, Zhice Xu1, Huangtian Yang2,6, Xiyuan Lu1
  • 1Institute for Fetology, First Hospital of Soochow University, Suzhou, China
  • 2CAS Key Laboratory of Tissue Microenvironment and Tumor, Laboratory of Molecular Cardiology, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences (CAS), CAS, Shanghai, China
  • 3Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health, The First Affiliated Hospital, Zhejiang University, Hangzhou, China
  • 4Institute of Translational Medicine, Zhejiang University, Hangzhou, China
  • 5Department of Internal Medicine, University of California Davis, Davis, CA 95616, USA
  • 6Institute for Stem Cell and Regeneration, CAS, Beijing, China
* Equal contribution
Received: November 20, 2019Accepted: March 29, 2020Published: April 28, 2020
https://doi.org/10.18632/aging.103088

Copyright © 2020 Liu et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

Human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) have great potential in biomedical applications. However, the immature state of cardiomyocytes obtained using existing protocols limits the application of hPSC-CMs. Unlike adult cardiac myocytes, hPSC-CMs generate ATP through an immature metabolic pathway—aerobic glycolysis, instead of mitochondrial oxidative phosphorylation (OXPHOS). Hence, metabolic switching is critical for functional maturation in hPSC-CMs. Peroxisome proliferator-activated receptor gamma coactivator 1α (PGC-1α) is a key regulator of mitochondrial biogenesis and metabolism, which may help promote cardiac maturation during development. In this study, we investigated the effects of PGC-1α and its activator ZLN005 on the maturation of human embryonic stem cell-derived cardiomyocyte (hESC-CM). hESC-CMs were generated using a chemically defined differentiation protocol and supplemented with either ZLN005 or DMSO (control) on differentiating days 10 to 12. Biological assays were then performed around day 30. ZLN005 treatment upregulated the expressions of PGC-1α and mitochondrial function-related genes in hESC-CMs and induced more mature energy metabolism compared with the control group. In addition, ZLN005 treatment increased cell sarcomere length, improved cell calcium handling, and enhanced intercellular connectivity. These findings support an effective approach to promote hESC-CM maturation, which is critical for the application of hESC-CM in disease modeling, drug screening, and engineering cardiac tissue.