Metabolic Regulation of Cardiac Differentiation and Maturation in Pluripotent Stem Cells: A Lesson from Heart Development

Abstract

The heart, one of the more complex organs, is composed from a number of differentiated cells. In general, researchers consider that the cardiac cells are derived from the same origin as mesodermal cells, except neural crest cells. However, as the developmental stages proceed, cardiac mesodermal cells are differentiated into various types of cells via cardiac progenitors and demonstrate different programming in transcriptional network and epigenetic regulation in a spatiotemporal manner. In fact, the metabolic feature also changes dramatically during heart development and cardiac differentiation. Researchers reported that each type of cell exhibits different metabolic features that can be used to specifically identify them. Metabolism is a critical process for generating energy and biomass in all living cells and organisms and has been long regarded as a passenger, rather than an active driver, for intracellular status. However, recent studies revealed that metabolism influences self-renewal and cell fate specification via epigenetic changes directly or indirectly. Metabolism mirrors the physiological status of the cell and endogenous cellular activity; therefore, understanding the metabolic signature of each cell type serves as a guide for innovative methods of selecting and differentiating desired cell types. Stem cell biology and developmental biology hold great promise for cardiac regenerative therapy, for which, successful strategy depends on the precise translation of the philosophy of cardiac development in the early embryo to the cell production system. In this review, we focus on the metabolism during heart development and cardiac differentiation and discuss the next challenge to unlock the potential of cell biology for regenerative therapy based on metabolism.

Mitochondrial Biogenesis, Mitochondrial Dynamics, and Mitophagy in the Maturation of Cardiomyocytes

“…As development proceeds, mitochondria occupy ~20–40% of adult CM volume [ 120 ]. It has been documented that in PSC-CMs, the changes in energy metabolism have important impacts on the ability of CMs to proliferate during early cardiac development, as well as when CMs terminally differentiate during later development [ 121 ]. A previous study reported that an appropriate metabolic shift from aerobic glycolysis to OXPHOS would in turn improve metabolic and functional maturation of human PSC-CMs (hPSC-CMs) [ 122 ].…”

Enhanced glucose metabolism through activation of HIF-1α covers the energy demand in a rat embryonic heart primordium after heartbeat initiation

“…Glycolysis has been reported to be a major source of energy in mesodermal and cardiac progenitor cells during early cardiac development 10 – 12 . The oxygen supply to the embryo is limited to diffusion from the placenta until fetal circulation is formed, and thus it is reasonable that glycolysis, which does not require oxygen to produce ATP, plays a central role in energy production in the heart primordium.…”

“…The oxygen supply to the embryo is limited to diffusion from the placenta until fetal circulation is formed, and thus it is reasonable that glycolysis, which does not require oxygen to produce ATP, plays a central role in energy production in the heart primordium. In contrast, it has been acknowledged that mitochondrial oxidative phosphorylation (OXPHOS), which can produce large amounts of ATP compared with those produced by anerobic glycolysis under the condition of a sufficient supply of oxygen and energy substrates, contributes less to energy metabolism in the embryonic heart than that in the matured heart 10 – 12 . In fact, cristae density and the number of mitochondria in cardiomyocytes have been reported to be smaller in the embryonic heart than in the matured heart 12 – 14 , suggesting less reliance on mitochondrial OXPHOS for the production of ATP in cardiac progenitor cells or cardiomyocytes in the embryo.…”

“…In contrast, it has been acknowledged that mitochondrial oxidative phosphorylation (OXPHOS), which can produce large amounts of ATP compared with those produced by anerobic glycolysis under the condition of a sufficient supply of oxygen and energy substrates, contributes less to energy metabolism in the embryonic heart than that in the matured heart 10 – 12 . In fact, cristae density and the number of mitochondria in cardiomyocytes have been reported to be smaller in the embryonic heart than in the matured heart 12 – 14 , suggesting less reliance on mitochondrial OXPHOS for the production of ATP in cardiac progenitor cells or cardiomyocytes in the embryo. However, it remains unclear whether mitochondria play any roles in response to increased energy demand to initiate excitation–contraction coupling in the developing heart primordium.…”

Proteomic Analysis of Exosomes during Cardiogenic Differentiation of Human Pluripotent Stem Cells

“…A shift in metabolism is well documented for differentiating stem cells from glycolysis in the pluripotent state to oxidative phosphorylation (OxPhos) [90,91]. Accordingly, S0 and S1 rely on glycolysis and-to a lesser extent-glutamine oxidation for metabolism.…”