Frequency of mononuclear diploid cardiomyocytes underlies natural variation in heart regeneration

Abstract

Adult mammalian cardiomyocyte regeneration after injury is thought to be minimal. Mononuclear diploid cardiomyocytes (MNDCMs), a relatively small subpopulation in the adult heart, may account for the observed degree of regeneration, but this has not been tested. We surveyed 120 inbred mouse strains and found that the frequency of adult mononuclear cardiomyocytes was surprisingly variable (>7-fold). Cardiomyocyte proliferation and heart functional recovery after coronary artery ligation both correlated with pre-injury MNDCM content. Using genome-wide association, we identified Tnni3k as one gene that influences variation in this composition and demonstrated that Tnni3k knockout resulted in elevated MNDCM content and increased cardiomyocyte proliferation after injury. Reciprocally, overexpression of Tnni3k in zebrafish promoted cardiomyocyte polyploidization and compromised heart regeneration. Our results corroborate the relevance of MNDCMs in heart regeneration. Moreover, they imply that intrinsic heart regeneration is not limited nor uniform in all individuals, but rather is a variable trait influenced by multiple genes.

Cardiomyocyte cell cycling, maturation, and growth by multinucleation in postnatal swine

“…Lack of mononucleated-diploid and cell cycling CMs has been proposed as a mechanism for loss of cardiac regenerative capacity in adult mammals. 5,12 The innate capacity in zebrafish and newts for heart regeneration throughout life has been linked to presence of mononucleateddiploid CMs, 38 while polyploidization of CM nuclei inhibits cardiac regeneration in zebrafish. 12,39 Further, mononucleated-diploid CMs were used as a proxy for regenerative potential in assessing the impact of evolutionary ectotherm to endotherm transition on cardiac regenerative capacity.…”

“…5,12 The innate capacity in zebrafish and newts for heart regeneration throughout life has been linked to presence of mononucleateddiploid CMs, 38 while polyploidization of CM nuclei inhibits cardiac regeneration in zebrafish. 12,39 Further, mononucleated-diploid CMs were used as a proxy for regenerative potential in assessing the impact of evolutionary ectotherm to endotherm transition on cardiac regenerative capacity. 14 Rodent hearts undergo cell cycle arrest in the first postnatal week concurrent with loss of heart regenerative capacity, and cell cycling is also negligible in the non-regenerative adult human heart.…”

Postnatal undernutrition alters adult female mouse cardiac structure and function leading to limited exercise capacity

“…The capacity of cardiomyocytes for division is retained until the cells undergo terminal differentiation, and is associated with the cells becoming binucleated and/or polyploid (Patterson et al . ). In humans, cardiomyocyte numbers increase until 20 years of age by some studies (Mollova et al .…”

“…Postnatal growth is primarily through hypertrophy of existing cardiomyocytes accompanied by varying degrees of cell division, nuclear division, and/or polyploidization depending on species. The capacity of cardiomyocytes for division is retained until the cells undergo terminal differentiation, and is associated with the cells becoming binucleated and/or polyploid (Patterson et al 2017). In humans, cardiomyocyte numbers increase until 20 years of age by some studies (Mollova et al 2013), albeit at low rates after the first year of life; the number of mononucleated cells remains relatively constant, whereas the number of polyploid nuclei increases into adulthood (Mollova et al 2013).…”

A Regeneration Toolkit

“…For instance, increased CNS axonal regenerative capacity has been reported in CAST/Ei strain mice as compared to more commonly used laboratory strains like C57BL/6 (Omura et al, 2015). Moreover, a recent work reported intrinsic variability in cardiomyocyte proliferation and functional recovery after ischemic myocardial injury between dozens of strains of inbred mice (Patterson et al, 2017). While this study implicated a polymorphism that appears to contribute to this variability, the genetic bases for regenerative capacity may well be challenging to methodically pick apart through strain comparisons and mapping of genetic modifier loci.…”