Abstract
Cardiac maturation lays the foundation for postnatal heart development and disease, yet little is known about the contributions of the microenvironment to cardiomyocyte maturation. By integrating single-cell RNA-sequencing data of mouse hearts at multiple postnatal stages, we construct cellular interactomes and regulatory signaling networks. Here we report switching of fibroblast subtypes from a neonatal to adult state and this drives cardiomyocyte maturation. Molecular and functional maturation of neonatal mouse cardiomyocytes and human embryonic stem cell-derived cardiomyocytes are considerably enhanced upon co-culture with corresponding adult cardiac fibroblasts. Further, single-cell analysis of in vivo and in vitro cardiomyocyte maturation trajectories identify highly conserved signaling pathways, pharmacological targeting of which substantially delays cardiomyocyte maturation in postnatal hearts, and markedly enhances cardiomyocyte proliferation and improves cardiac function in infarcted hearts. Together, we identify cardiac fibroblasts as a key constituent in the microenvironment promoting cardiomyocyte maturation, providing insights into how the manipulation of cardiomyocyte maturity may impact on disease development and regeneration.
Highlights
Cardiac maturation lays the foundation for postnatal heart development and disease, yet little is known about the contributions of the microenvironment to cardiomyocyte maturation
Gene ontology (GO) analysis showed that genes highly expressed in State 1 were enriched in functions related to RNA splicing, cell cycle phase transition, etc. (Fig. 1g)
Genes highly expressed in States 2 and 7 were enriched in functions related to cardiac muscle development, whereas those expressed in States 8 and 9 were associated with heart contraction and ATP metabolic process (Fig. 1h–j)
Summary
Cardiac maturation lays the foundation for postnatal heart development and disease, yet little is known about the contributions of the microenvironment to cardiomyocyte maturation. Many hurdles still lie ahead on their road into the clinic Adverse effects, such as arrhythmia and teratoma formation, were frequently observed in studies using pluripotent stem cell-derived cardiomyocytes due to their immature nature[1,4]. A panoply of factors, including transcription factors, microRNAs, as well as endothelial nitric oxide synthase (eNOS), were suggested to play crucial roles in the maturation of the conduction system in the heart, or in controlling other aspects of cardiomyocyte biology, such as metabolism, cell size, contractility, and proliferation[20,24,25] These and other studies together suggested multi-layered regulatory networks in cardiomyocyte maturation, urging for more detailed and comprehensive characterization of the underlying molecular events. Manipulation of fibroblasts or downstream signaling pathways regulates cardiomyocyte maturity, providing potentially viable strategies to improve outcomes of stem cell-based or cellfree therapies
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