Abstract
BackgroundHuman induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) hold great promise for regenerative medicine and in drugs screening. Despite displaying key cardiomyocyte phenotypic characteristics, they more closely resemble fetal/neonatal cardiomyocytes and are still immature; these cells mainly rely on glucose as a substrate for metabolic energy, while mature cardiomyocytes mainly employ oxidative phosphorylation of fatty acids. Studies showed that the alteration of metabolism pattern from glycolysis to oxidative phosphorylation improve the maturity of hiPSC-CMs. As a transcription factor, accumulating evidences showed the important role of NRF2 in the regulation of energy metabolism, which directly regulates the expression of mitochondrial respiratory complexes. Therefore, we hypothesized that NRF2 is involved in the maturation of hiPSC-CMs.MethodsThe morphological and functional changes related to mitochondria and cell maturation were analyzed by knock-down and activation of NRF2.ResultsThe results showed that the inhibition of NRF2 led to the retardation of cell maturation. The activation of NRF2 leads to a more mature hiPSC-CMs phenotype, as indicated by the increase of cardiac maturation markers, sarcomere length, calcium transient dynamics, the number and fusion events of mitochondria, and mitochondrial respiration. Bioinformatics analysis showed that in addition to metabolism-related genes, NRF2 also activates the expression of myocardial ion channels.ConclusionsThese findings indicated that NRF2 plays an important role in the maturation of hiPSC-CMs. The present work provides greater insights into the molecular regulation of hiPSC-CMs metabolism and theoretical basis in drug screening, disease modeling, and alternative treatment.
Highlights
Human induced pluripotent stem cell-derived cardiomyocytes hold great promise for regenerative medicine and in drugs screening
Zhang et al Stem Cell Research & Therapy (2021) 12:208 (Continued from previous page). These findings indicated that Nuclear factor erythroid 2 p45-related factor 2 (NRF2) plays an important role in the maturation of hiPSC-CMs
The calcium transient kinetics were assessed during contraction of hiPSC-CMs with Fluo-4 AM. These results showed that reduced peak amplitude, upstroke, and decay velocities were obtained in the significantly down-regulated in the NRF2-inhibited hiPSCCMs (siNRF2) hiPSC-CMs compared with the siNC hiPSCCMs (Fig. S2A-D), indicating that the calcium handling system was weakened
Summary
Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) hold great promise for regenerative medicine and in drugs screening. Despite displaying key cardiomyocyte phenotypic characteristics, they more closely resemble fetal/neonatal cardiomyocytes and are still immature; these cells mainly rely on glucose as a substrate for metabolic energy, while mature cardiomyocytes mainly employ oxidative phosphorylation of fatty acids. We hypothesized that NRF2 is involved in the maturation of hiPSC-CMs. Because of the irreparability of cardiac tissue and the scarcity of organs for donation, human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) hold great potential for the treatment of myocardial injury [1]. The mitochondria of embryonic cardiomyocytes are underdeveloped; these cells mainly rely on glucose as a substrate for metabolic energy, while mature cardiomyocytes mainly employ oxidative phosphorylation of fatty acids to fulfill the rising demand for energy [6]. Studies showed that the alteration of metabolism pattern from glycolysis to oxidative phosphorylation improves the maturity of hiPSC-CMs [7, 8]
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