Building and re-building the heart by cardiomyocyte proliferation

Abstract

The adult human heart does not regenerate significant amounts of lost tissue after injury. Rather than making new, functional muscle, human hearts are prone to scarring and hypertrophy, which can often lead to fatal arrhythmias and heart failure. The most-cited basis of this ineffective cardiac regeneration in mammals is the low proliferative capacity of adult cardiomyocytes. However, mammalian cardiomyocytes can avidly proliferate during fetal and neonatal development, and both adult zebrafish and neonatal mice can regenerate cardiac muscle after injury, suggesting that latent regenerative potential exists. Dissecting the cellular and molecular mechanisms that promote cardiomyocyte proliferation throughout life, deciphering why proliferative capacity normally dissipates in adult mammals, and deriving means to boost this capacity are primary goals in cardiovascular research. Here, we review our current understanding of how cardiomyocyte proliferation is regulated during heart development and regeneration.

Keywords: Cardiomyocyte; Heart regeneration; Proliferation.

Fig. 1.

Cardiomyocyte contributions to the formation, growth and sculpting of mature cardiac structures. (A) Formation of trabecular muscle in mice begins at approximately E10.5, when inductive signals from the endocardium (not shown) stimulate cell division in the myocardium (orange cells). Newly divided cardiomyocytes (pink cells) form muscular ridges known as trabeculae that are thought to strengthen contraction and improve myocardial oxygenation. (B) By E13-E14, the ventricular wall thickens substantially as cardiomyocytes proliferate (pink cells) in the outer layers of the myocardium to form compact muscle. (C) In zebrafish, the ventricular wall does not thicken until 6-8 weeks post-fertilization (wpf), when rare trabecular muscle cardiomyocytes (pink cells) in the chamber lumen emerge through the primordial wall (orange) and proliferate to cover the ventricle in a cortical muscle layer.

Fig. 2.

Cell intrinsic and extrinsic factors that regulate the cardiomyocyte cell cycle. After birth, mammalian cardiomyocytes transition from a primarily proliferative mode of growth to a hypertrophic program characterized by the reduction of cell cycling. Regulatory factors that promote cell division are downregulated whereas inhibitory factors increase in expression. These proposed factors include both cell-intrinsic elements (e.g. Meis1, Yap, miRNAs) and extrinsic signals (e.g. oxygen availability, macrophage-derived factors).

Fig. 3.

Neuregulin 1/ErbB2 signaling during cardiac growth and regeneration. (A) In mice, the transition from hyperplastic to hypertrophic growth during the neonatal period correlates with a reduction in levels of the neuregulin 1 co-receptor ErbB2. The expression of constitutively active ErbB2 (caErbB2) in cardiomyocytes can thus extend or re-activate cardiomyocyte cell division and hypertrophy, resulting in cardiomegaly. (B) In zebrafish, the induction of endogenous neuregulin 1 (Nrg1) production after injury (e.g. apical amputation) is associated with cardiomyocyte proliferation and heart regeneration. The transgenic overexpression of Nrg1 in cardiomyocytes causes continuous hyperplastic growth in uninjured adult hearts.

Fig. 4.

Hippo signaling during heart development and regeneration. (A) Hippo signaling restricts the ability of Yap to promote cardiomyocyte proliferation in developing mice. Mice with Nkx2-5 regulatory sequence-driven conditional knockout of Yap (YapCKO) have hypoplastic hearts, whereas Nkx2-5-driven conditional deletion of the Hippo signaling component Salv (SalvCKO) or expression of a constitutively active Yap (caYap) in β-myosin heavy chain-expressing cells causes myocardial hyperplasia. (B) The manipulation of Yap activity after birth can prevent or extend the capacity for compensatory cardiomyocyte proliferation after injury. Wild-type mice that undergo myocardial infarction at P2 exhibit increased cardiomyocyte proliferation with limited scarring, whereas mice infarcted at P7 or P8 show prominent scarring. The α-myosin heavy chain-driven conditional knock-out of Yap (YapCKO) in cardiomyocytes increases scar formation after infarction at P2, whereas α-myosin heavy chain-driven conditional knock-out of Salv (SalvCKO) or the expression of constitutively active Yap (caYap) in α-myosin heavy chain-expressing cells each increase cardiomyocyte division and reduce scarring after apical resection and infarction, respectively, at P7-P8. WT, wild type.

Fig. 5.

A model of the effects of oxygen and ROS on cardiomyocyte proliferation. In mice, the transition from relatively hypoxic conditions in utero to atmospheric oxygen after birth correlates with the accumulation of reactive oxygen species and DNA damage in cardiomyocytes. One model proposes that cardiomyocyte withdrawal from the cell cycle during the switch from hyperplastic to hypertrophic growth is a response to this damage, with further proliferation in adulthood being retained in only a small pool of hypoxic cardiomyocytes (outlined by dashed line). By contrast, in zebrafish (not shown), which thrive in relatively hypoxic conditions, cardiomyocytes do not lose the capacity for proliferation; this is retained through to adulthood.