Cardiomyocyte-fibroblast crosstalk in the postnatal heart

Abstract

During the postnatal period in mammals, the heart undergoes significant remodeling in response to increased circulatory demands. In the days after birth, cardiac cells, including cardiomyocytes and fibroblasts, progressively lose embryonic characteristics concomitant with the loss of the heart's ability to regenerate. Moreover, postnatal cardiomyocytes undergo binucleation and cell cycle arrest with induction of hypertrophic growth, while cardiac fibroblasts proliferate and produce extracellular matrix (ECM) that transitions from components that support cellular maturation to production of the mature fibrous skeleton of the heart. Recent studies have implicated interactions of cardiac fibroblasts and cardiomyocytes within the maturing ECM environment to promote heart maturation in the postnatal period. Here, we review the relationships of different cardiac cell types and the ECM as the heart undergoes both structural and functional changes during development. Recent advances in the field, particularly in several recently published transcriptomic datasets, have highlighted specific signaling mechanisms that underlie cellular maturation and demonstrated the biomechanical interdependence of cardiac fibroblast and cardiomyocyte maturation. There is increasing evidence that postnatal heart development in mammals is dependent on particular ECM components and that resulting changes in biomechanics influence cell maturation. These advances, in definition of cardiac fibroblast heterogeneity and function in relation to cardiomyocyte maturation and the extracellular environment provide, support for complex cell crosstalk in the postnatal heart with implications for heart regeneration and disease mechanisms.

Keywords: cardiac fibroblast; cardiomyocyte; cell signaling; extracellular matrix; heart regeneration; postnatal heart.

FIGURE 1

Cardiomyocyte-Fibroblast cellular crosstalk in the developing and diseased heart. During the embryonic period, cardiac fibroblasts remain immature while cardiomyocytes experience high rates of proliferation. At birth, fibroblasts become activated and signal for cardiomyocytes to exit the cell cycle, switch to hypertrophic growth and undergo metabolic transition. Between P7 and P30, fibroblasts return to their quiescent state while cardiomyocytes further their maturity by switching their expression to adult sarcomeric proteins and mature electrophysiology. After injury, fibroblasts become activated and secrete pathogenic ECM proteins while cardiomyocytes experience hypoxia induced autophagy and eventually cell death. Created with BioRender.com.

FIGURE 2

Extracellular matrix mechanical effects on cardiomyocytes and fibroblasts in development and disease. The extracellular matrix (ECM) plays a role in the maturation of cardiomyocytes and function of fibroblasts. After birth, the ECM undergoes mechanical changes, specifically the increased stiffness of the matrix due to changes in the ECM protein composition, secreted by fibroblasts. ECM stiffness increases from neonatal to adulthood, with the highest stiffness occurring during disease, which results in fibrosis and scarring. The compositional changes that occur at each stage are listed, with green as increase and red as decrease in ECM proteins. Created with BioRender.com.