Developmental lineage of human pluripotent stem cell-derived cardiac fibroblasts affects their functional phenotype.
Martha E FloySophie E GivensOriane B MatthysTaylor D MateykaCharles M KerrAlexandra B SteinbergAna C SilvaJianhua ZhangYing MeiBrenda M OgleTodd C McDevittTimothy J KampSean P PalecekPublished in: FASEB journal : official publication of the Federation of American Societies for Experimental Biology (2021)
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.
Keyphrases
- extracellular matrix
- endothelial cells
- stress induced
- gene expression
- induced pluripotent stem cells
- left ventricular
- pluripotent stem cells
- public health
- transcription factor
- induced apoptosis
- systemic sclerosis
- chronic kidney disease
- atrial fibrillation
- cell death
- signaling pathway
- climate change
- heat stress
- epithelial mesenchymal transition