Abstract
Pluripotent stem cells (PSCs) can undergo unlimited self-renewal and can differentiate into all the cell types present in our body, including cardiomyocytes. Therefore, PSCs can be an excellent source of cardiomyocytes for future regenerative medicine and medical research studies. However, cardiomyocytes obtained from PSC differentiation culture are regarded as immature structurally, electrophysiologically, metabolically, and functionally. Mitochondria are organelles responsible for various cellular functions such as energy metabolism, different catabolic and anabolic processes, calcium fluxes, and various signaling pathways. Cells can respond to cellular needs to increase the mitochondrial mass by mitochondrial biogenesis. On the other hand, cells can also degrade mitochondria through mitophagy. Mitochondria are also dynamic organelles that undergo continuous fusion and fission events. In this review, we aim to summarize previous findings on the changes of mitochondrial biogenesis, mitophagy, and mitochondrial dynamics during the maturation of cardiomyocytes. In addition, we intend to summarize whether changes in these processes would affect the maturation of cardiomyocytes. Lastly, we aim to discuss unanswered questions in the field and to provide insights for the possible strategies of enhancing the maturation of PSC-derived cardiomyocytes.
Highlights
Introduction to MitochondriaMitochondria are membrane-bound organelles found in the cytoplasm of eukaryoticMatured CMs have an improved alignment of sarcomeres, longer sarcomeres, and existence of ttubules and become multi-nucleated
More detailed investigation is needed to elucidate the exact role of TFAM and TFB2M in CM maturation. These results showed that mitochondrial biogenesis is essential for CM maturation (Figure 2) and unveiled a new strategy to improve the maturation of Pluripotent stem cells (PSCs)-CMs and to generate more physiologically mature CMs for drug screening, disease modeling, and therapeutic purposes
These results showed that mitochondrial biogenesis is essential for CM maturation (Figure 2) and unveiled a new strategy to improve the maturation of PSCCMs and to generate more physiologically mature CMs for drug screen9ionfg1,8disease modeling, and therapeutic purposes
Summary
The mammalian heart is the first differentiated and functional organ in the developing embryo. The following changes occur as CMs mature ex vivo: (i) adult cardiac genes instead of fetal cardiac genes are expressed; (ii) cell size increases and cell shape changes from circular to rod shape; (iii) sarcomere length increases and t-tubules are formed; (iv) electrophysiologically, action potential (AP) upstroke becomes faster, AP duration increases, maximum diastolic potential becomes more hyperpolarized, and diastolic depolarization slope decreases until the cells become electrically quiescent yet excitable; (v) mitochondria shape changes from small and round to firstly slender and long and subsequently ovular; (vi) metabolically, cells rely on oxidative phosphorylation (OXPHOS) instead of glycolysis for ATP production; and (vii) metabolic substrate changes from glucose to fatty acid [14,15] (Figure ??). Matured CMs have an improved alignment of sarcomeres, longer sarcomeres, and existence of ttubules and become multi-nucleated They have enhanced calcium handling, electrophysiology, and metabolism. APs, action potentials; CaTs, calcium transients; OXPHOS, oxidative phosphorylation; β-Ox, β-oxidation
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