The Influence of Fibroblast Microenvironment on the Differentiation and Maturation of Stem Cell-Derived...

Induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) have emerged as a promising cell source for myocardial repair. However, iPSC-CMs generated in vitro exhibit an immature phenotype resembling the fetal stage in terms of morphology, electrophysiology, and metabolic properties, falling significantly short of the maturity observed in adult cardiomyocytes [1]. The differentiation and maturation of cardiomyocytes do not occur in isolation but are progressively realized within a specific cellular microenvironment. Cardiac fibroblasts (CFs) account for approximately 20%-30% of the total cell population in the heart. CFs play pivotal roles in cardiac development, homeostasis, and pathological remodeling through the secretion of various soluble factors, the synthesis and remodeling of the extracellular matrix (ECM), and the establishment of physical and functional intercellular connections (Fig. 1). CFs construct specific microenvironments that significantly influence the lineage commitment, early expansion, and subsequent structural and functional maturation of iPSC-CMs. Thus, the CF microenvironment acts as a crucial extrinsic factor regulating the fate of stem cell-derived cardiomyocytes.