Cardiomyocyte Proliferation and Maturation: Two Sides of the Same Coin for Heart Regeneration

Abstract

In the past few decades, cardiac regeneration has been the central target for restoring the injured heart. In mammals, cardiomyocytes are terminally differentiated and rarely divide during adulthood. Embryonic and fetal cardiomyocytes undergo robust proliferation to form mature heart chambers in order to accommodate the increased workload of a systemic circulation. In contrast, postnatal cardiomyocytes stop dividing and initiate hypertrophic growth by increasing the size of the cardiomyocyte when exposed to increased workload. Extracellular and intracellular signaling pathways control embryonic cardiomyocyte proliferation and postnatal cardiac hypertrophy. Harnessing these pathways could be the future focus for stimulating endogenous cardiac regeneration in response to various pathological stressors. Meanwhile, patient-specific cardiomyocytes derived from autologous induced pluripotent stem cells (iPSCs) could become the major exogenous sources for replenishing the damaged myocardium. Human iPSC-derived cardiomyocytes (iPSC-CMs) are relatively immature and have the potential to increase the population of cells that advance to physiological hypertrophy in the presence of extracellular stimuli. In this review, we discuss how cardiac proliferation and maturation are regulated during embryonic development and postnatal growth, and explore how patient iPSC-CMs could serve as the future seed cells for cardiac cell replacement therapy.

Silencing of Sphingosine kinase 1 Affects Maturation Pathways in Mouse Neonatal Cardiomyocytes

“…Cardiac myocytes undergo dynamic changes during fetal and postnatal development, reaching a mature phenotype shortly after birth [ 23 , 24 ]. Neonatal mouse CMs exit the cell cycle within the first week of life and undergo the final stage of differentiation [ 25 ].…”

“…Moreover, Sphk1 silencing markedly induced the expression of Ndufs1 (a leading edge gene in pathways related to mitochondrial activity), which encodes one of the subunits of NADH:ubiquinone oxidoreductase, an enzyme engaged in the mitochondrial oxidative metabolism, which is the main source of adenosine triphosphate (ATP) in high-energy-demanding, terminally differentiated CMs [ 31 ]. Cell cycle-related genes such Pds5a and Ccne2 , encoding Sister chromatid cohesion protein PDS5 homolog A and G1/S-specific cyclin-E2 , respectively, have well-known roles in cell division [ 24 , 32 ]. Their downregulation in Sphk1 -lacking CMs indicates the diminished proliferation potential of such cells.…”

“…Postnatal cardiomyocyte development is orchestrated by a complex net of signaling pathways [ 23 , 24 , 26 ]. However, extracellular signaling initiated by thyroid hormone, Vegf or insulin/Igf1 all merge with downstream Akt signaling, making this serine–threonine kinase a central regulator of CM maturation.…”

Decoding Genetics of Congenital Heart Disease Using Patient-Derived Induced Pluripotent Stem Cells (iPSCs)

“…In addition to cell-autonomous inherited cardiac disease such as long QT syndrome ( Moretti et al, 2010 ; Itzhaki et al, 2011 ), ventricular tachycardia ( Zhang et al, 2014 ; Sleiman et al, 2020 ) and dilated cardiomyopathy ( Sun et al, 2012 ; Hinson et al, 2015 ), patient iPSCs have been employed to model several types of CHD, including BAV and calcific aortic valve disease (CAVD) ( Theodoris et al, 2015 ), supravalvular aortic stenosis (SVAS) ( Ge et al, 2012 ), cardiac septal defects ( Ang et al, 2016 ), Barth syndrome ( Wang et al, 2014 ), and HLHS ( Hrstka et al, 2017 ; Yang et al, 2017 ; Miao et al, 2020 ; Table 2 ). Human iPSCs can be differentiated to the desired cardiovascular cell types relevant for studying different CHD ( Protze et al, 2019 ), though the immaturity of iPSC-derived cardiomyocytes (iPSC-CMs) continues to be a challenge for recapitulating the physiological scenarios in the heart ( Karbassi et al, 2020 ; Zhao et al, 2020b ). Robust cardiac differentiation protocols have been optimized to generate subtype-specific (atrial, ventricular and nodal) cardiomyocytes for precision disease modeling ( Zhang et al, 2011 ; Lee et al, 2017 ; Protze et al, 2017 ; Ren et al, 2019 ; Liang et al, 2020 ; Zhao et al, 2020a ).…”

“…Human iPSC-CMs are fetal-like cardiomyocytes and show immature structural and physiological characteristics. For example, iPSC-CMs do not have mature structures of myofibrils and T-tubule, and they are misaligned compared to rod-shape adult cardiomyocytes ( Karbassi et al, 2020 ; Zhao et al, 2020b ). Enormous efforts have been made to promote the structural and functional maturation of iPSC-CMs, including the addition of thyroid and glucocorticoid hormones ( Parikh et al, 2017 ), physical and electrical conditioning ( Ronaldson-Bouchard et al, 2018 ), and co-culture with stromal cells in 3D cardiac microtissues ( Giacomelli et al, 2020 ).…”