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.
Highlights
Human cardiovascular diseases continue to cause major health and economic burden worldwide [1, 2]
The proliferator-activated receptor gamma coactivator 1 (PGC-1) family consists of a group of transcriptional coregulators that coordinates mitochondrial biogenesis and is highly expressed in cardiac tissue [26]
To investigate which PGC-1 family member may facilitate hPSC-CMs maturation, we examined the expression profile of PGC-1 family members during cardiac differentiation of hESCs
Summary
Human cardiovascular diseases continue to cause major health and economic burden worldwide [1, 2]. Cardiomyocytes differentiated from human pluripotent stem cells (hPSC-CMs), including both embryonic stem cell-derived cardiomyocytes (hESC-CMs) and induced pluripotent stem cell-derived cardiomyocytes (hiPSCCMs), provide an enormous potential for the development of tissue engineering, drug screening, and cardiac disease www.aging-us.com modeling platforms [3,4,5]. Acquiring mature hiPSC-CMs, remains a significant and challenging problem. Strategies that help promote the maturation of hPSC-CMs are indispensable for the application of hPSC-CMs. Several approaches have been reported to enhance hPSC-CMs’ maturation, such as longterm culture, bioelectrical stimulation, mechanical stretch, biochemical stimulation, and the incorporation of CMs into 3D tissue constructs [9,10,11,12,13]; since these methods are time consuming, expensive, and technically challenging, they are not suitable for widespread adoption. We report a rapid, simple, and affordable method to promote the maturation of hPSC-CMs
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