Abstract
Cardiomyocyte (CM) maturation in mammals is accompanied by a sharp decline in their proliferative and regenerative potential shortly after birth. In this study, we explored the role of the mechanical properties of the underlying matrix in the regulation of CM maturation. We show that rat and mouse neonatal CMs cultured on rigid surfaces exhibited increased myofibrillar organization, spread morphology, and reduced cell cycle activity. In contrast, compliant elastic matrices induced features of CM dedifferentiation, including a disorganized sarcomere network, rounding, and conspicuous cell-cycle re-entry. The rigid matrix facilitated nuclear division (karyokinesis) leading to binucleation, while compliant matrices promoted CM mitotic rounding and cell division (cytokinesis), associated with loss of differentiation markers. Moreover, the compliant matrix potentiated clonal expansion of CMs that involves multiple cell divisions. Thus, the compliant microenvironment facilitates CM dedifferentiation and proliferation via its effect on the organization of the myoskeleton. Our findings may be exploited to design new cardiac regenerative approaches.
Highlights
During the early postnatal period, cardiomyocytes (CMs) undergo a switch from a proliferative, hyperplastic mode to non-proliferative, hypertrophic growth that persists throughout life (Li et al, 1996; Soonpaa et al, 1996; Soonpaa and Field, 1998)
Proliferating CMs were observed on all tested matrices (Ki67+/cardiac Troponin T (cTnT)+, and PH3+/Myosin heavy chain (MHC)+) (Figure 1E,F, respectively)
A closer examination of CMs derived from the Myh6 lineage that were grown on the 20 kPa matrix and lost cTnT and/or MHC expression, revealed clusters of cells, suggesting that these cells were derived from a common CM that underwent multiple cell divisions (Figure 5—figure supplement 1)
Summary
During the early postnatal period, cardiomyocytes (CMs) undergo a switch from a proliferative, hyperplastic mode to non-proliferative, hypertrophic growth that persists throughout life (Li et al, 1996; Soonpaa et al, 1996; Soonpaa and Field, 1998). Yahalom-Ronen et al.’s findings suggest that the stiffness of the matrix that surrounds heart muscle cells regulates their ability to divide and mature In the future, these findings may pave the way towards the development of soft scaffolds that can stimulate the regeneration of adult human heart. The lack of regenerative potential of the mammalian heart was challenged by Porrello and colleagues (Porrello et al, 2011), who showed that the neonatal murine heart displays a transient regenerative phase that diminishes within the first week after birth Both mammalian and zebrafish heart regeneration is characterized by increased CM proliferation associated with sarcomere disassembly, attributed to a CM dedifferentiation process (Poss, 2007; Jopling et al, 2010, 2011; Porrello et al, 2011). We suggest that the mechanical properties of the postnatal heart play a key role in the acquisition of the fully differentiated phenotype, and inhibition of the specialized contractile system in CMs could be used to promote CM dedifferentiation
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