Why the study?
Cardiac fibroblasts are an increasingly important therapeutic target, but how developmental lineage affects their transcriptional and functional properties needed to be described.
The developmental lineage of human pluripotent stem cell-derived cardiac fibroblasts dictates their functional phenotype, suggesting epicardial fibroblasts are better suited for modeling fibrotic diseases while second heart field fibroblasts may be preferable for regenerative therapies.
Should not yet change practice; leaves open whether lineage-specific hPSC-CFB differences persist in vivo or guide regenerative versus fibrosis-modeling applications.
Cardiac fibroblasts (CFBs) support heart function by secreting extracellular matrix (ECM) and paracrine factors, respond to stress associated with injury and disease, and therefore are an increasingly important therapeutic target. We describe how developmental lineage of human pluripotent stem cell-derived CFBs, epicardial (EpiC-FB), and second heart field (SHF-FB) impacts transcriptional and functional properties. Both EpiC-FBs and SHF-FBs exhibited CFB transcriptional programs and improved calcium handling in human pluripotent stem cell-derived cardiac tissues. We identified differences including in composition of ECM synthesized, secretion of growth and differentiation factors, and myofibroblast activation potential, with EpiC-FBs exhibiting higher stress-induced activation potential akin to myofibroblasts and SHF-FBs demonstrating higher calcification and mineralization potential. These phenotypic differences suggest that EpiC-FBs have utility in modeling fibrotic diseases while SHF-FBs are a promising source of cells for regenerative therapies. This work directly contrasts regional and developmental specificity of CFBs and informs CFB in vitro model selection.
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Floy et al. (2021) studied this question.
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