Early Regenerative Capacity in the Porcine Heart

Abstract

-The adult mammalian heart has limited ability to repair itself following injury. Zebrafish, newts and neonatal mice can regenerate cardiac tissue, largely by cardiac myocyte (CM) proliferation. It is unknown if hearts of young large mammals can regenerate. -We examined the regenerative capacity of the pig heart in neonatal animals (ages: 2, 3 or 14 days postnatal) after myocardial infarction (MI) or sham procedure. Myocardial scar and left ventricular function were determined by cardiac magnetic resonance (CMR) imaging and echocardiography. Bromodeoxyuridine pulse-chase labeling, histology, immunohistochemistry and Western blotting were performed to study cell proliferation, sarcomere dynamics and cytokinesis and to quantify myocardial fibrosis. RNA-sequencing was also performed. -After MI, there was early and sustained recovery of cardiac function and wall thickness in the absence of fibrosis in 2-day old pigs. In contrast, older animals developed full-thickness myocardial scarring, thinned walls and did not recover function. Genome wide analyses of the infarct zone revealed a strong transcriptional signature of fibrosis in 14-day old animals that was absent in 2-day old pigs, which instead had enrichment for cytokinesis genes. In regenerating hearts of the younger animals, up to 10% of CMs in the border zone of the MI showed evidence of DNA replication that was associated with markers of myocyte division and sarcomere disassembly. -Hearts of large mammals have regenerative capacity, likely driven by cardiac myocyte division, but this potential is lost immediately after birth.

Reactivation of Myc transcription in the mouse heart unlocks its proliferative capacity

“…[57][58][59] ). This decline in neonatal cardiac proliferative potential correlates with down-regulation of multiple genes involved in cell cycle 40,55,[60][61][62][63] , including endogenous Myc, which is high at P1 but significantly reduced by P5 ( Supplementary Fig. 6a).…”

Induction of cardiomyocyte proliferation and angiogenesis protects neonatal mice from pressure overload–associated maladaptation

“…Neonatal heart regeneration is mediated mainly by proliferation of preexisting cardiomyocytes and is supported by angiogenesis, macrophage infiltration, and innervation (8,9,11). Intriguingly, heart regeneration was reported in pigs and even in a human newborn after myocardial infarction (12)(13)(14). The neonatal cardiac regenerative capacity, however, is lost by P7 (7).…”

Stimulating ideas for heart regeneration: the future of nerve-directed heart therapy

“…In contrast, adult zebrafish hearts are capable of mounting an endogenous regenerative program and are able to completely regenerate their myocardium through cardiomyocyte proliferation following ventricular resection (Poss et al 2002). This regenerative potential was found to be conserved in the mammalian heart, but only for a brief time after birth in both neonatal mice and pigs (Ye et al 2018;Zhu et al 2018). These models of endogenous cardiac regeneration revealed that regeneration is mediated by the proliferation of the pre-existing cardiomyocytes.…”