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.

Transcriptional dynamics of the murine heart during perinatal development at single-cell resolution

“…While the referenced studies involved cardiomyocytes, our results would suggest that regulation of cell growth is an important aspect of maturation across all cardiac cell types. Evidence of the known switch from glycolysis to aerobic respiration and fatty acid metabolism in cardiomyocytes (Padula et al, 2021; Uscategui Calderon et al, 2023) could be seen in the results for ACM, VCM, and TCM, with the former being downregulated and the latter two upregulated with time.…”

“…Fibroblasts and atrial/ventricular cardiomyocytes showed by far the most genes with dynamic expression over pseudotime, potentially reflecting a greater degree of perinatal development compared to other cell types. Fibroblasts are known to have extensive postnatal proliferation and involvement in ECM remodelling, while cardiomyocytes undergo significant changes previously discussed including hypertrophic cell growth with concomitant cell cycle arrest, sarcomeric protein isoform switching, and a transition to aerobic respiration (Padula et al, 2021; Uscategui Calderon et al, 2023). Caution must be taken with this interpretation however, as we noted positive correlation between cell number and the number of dynamic genes found per cell type ( Figure S4 ).…”

Evidence of Histone H2A.Z Deacetylation and Cardiomyocyte Dedifferentiation in Infarcted/Tip60-depleted Hearts

“…Extracellular Matrix: Alterations in the extracellular matrix during cardiac development and after injury, which are dependent upon crosstalk between CMs and fibroblast sub-populations in the myocardium, are the subject of a recent outstanding review 64 . As discussed above in Figure 4, many of the ECM genes exhibiting increased expression after depleting Tip60 post-MI have previously been associated with transition toward a relatively soft neonatal-like matrix within which CMs can migrate and proliferate [15][16][17] .…”

“…An interesting possibility to consider is that matrix softening is enhanced by the >11-fold increase in Cthrc1 --perhaps the most differentially expressed gene in our dataset --encoding collagen triple helix repeat containing-1 protein, that not only has a crucial role in wound healing 54 , but has also been shown to limit the deposition of collagen matrix during arterial remodeling 65,66 and promote cellular migration 67 . An additional question regards how the ECM gene battery, expression of which is essentially specific to various fibroblast subpopulations in the myocardium 54 , transitions toward softness when Tip60 is depleted in CMs; while the transition toward soft ECM is likely regulated via crosstalk between the Wnt/β-catenin, Hippo/Yap and TGFβ pathways 64 , mechanistic details of signaling between these various cell types remains speculative.…”