Mechanisms of Cardiac Regeneration

Abstract

Adult humans fail to regenerate their hearts following injury, and this failure to regenerate myocardium is a leading cause of heart failure and death worldwide. Although all adult mammals appear to lack significant cardiac regeneration potential, some vertebrates can regenerate myocardium throughout life. In addition, new studies indicate that mammals have cardiac regeneration potential during development and very soon after birth. The mechanisms of heart regeneration among model organisms, including neonatal mice, appear remarkably similar. Orchestrated waves of inflammation, matrix deposition and remodeling, and cardiomyocyte proliferation are commonly seen in heart regeneration models. Understanding why adult mammals develop extensive scarring instead of regeneration is a crucial goal for regenerative biology.

The extracellular matrix in myocardial injury, repair, and remodeling

“…Considering that, much like in fish and amphibians, myocardial infarction in mammals also induces a marked upregulation of tenascin-C and fibronectin without stimulating remuscularization, it is unlikely that matrix-dependent actions are sufficient to activate a regenerative program. Myocardial regeneration likely requires not only a "regenerative" matrix profile, but also local secretion of a yet-undefined combination of cytokines and growth factors, and activation of pathways that enhance plasticity of progenitor cell populations (146). Third, in several cell therapy studies in mammalian models of cardiac injury, application of matrix-based patches containing progenitor cells showed enhanced effectiveness (147,148).…”

DNA methylation and chromatin dynamics during postnatal cardiomyocyte maturation

“…Unlike the urodele amphibians discussed in the previous section, adult anuran amphibians exhibited a different regenerative response (Rumyantsev, 1973;Uygur and Lee, 2016).…”

“…As another avenue for replenishment of cardiomyocytes after injury, it is important to consider the mechanisms of activation of endogenous cardiac regenerative capability. In fact, heart regeneration has been investigated in depth in the past 50 years in several amphibian, teleost and mammalian species (Carvalho and de Carvalho, 2010;Laflamme and Murry, 2011;Uygur and Lee, 2016). In higher vertebrates, compared to highly regenerative organs such as liver, bone, skeletal muscle or skin, the heart is one of the least regenerative organs.…”

“…Previous studies using apical resection and induced MI already showed that following development, adult mouse failed to regenerate following injury (Porrello et al, 2011b) (Porrello et al, 2013) (Haubner et al, 2012). It is important to notice that, while sharing the similar biological processes with neonatal mouse hearts following injury which involves initial formation of blood clot, infiltration of immune cells as well as deposition of extracellular matrix at the injured region, adult mouse hearts fail to activate the cardiomyocyte proliferation to compensate the loss of cardiac tissue, ending with extensive scar formation (Uygur and Lee, 2016), suggesting a developmental modification that regulates cardiomyocyte proliferation capacity after birth (Figure 1.2).…”

“…However, the adult frog heart failed to undergo full regeneration, leaving a partially regenerated and partially scarred heart tissue (Rumyantsev, 1973;Uygur and Lee, 2016). …”