Developmental lineage of human pluripotent stem cell-derived cardiac fibroblasts affects their functional phenotype
Martha E Floy1, Sophie E Givens2, Oriane B Matthys3,4
1Department of Chemical and Biological Engineering, University of Wisconsin-Madison, Madison, WI, USA.
Insights
Human pluripotent stem cell-derived cardiac fibroblasts (CFBs) from different developmental origins show distinct properties. Epicardial-derived CFBs model fibrosis, while second heart field-derived CFBs offer regenerative potential.
Area of Science:
- Cardiovascular Biology
- Stem Cell Biology
- Developmental Biology
Background:
- Cardiac fibroblasts (CFBs) are crucial for heart function, secreting extracellular matrix (ECM) and paracrine factors.
- CFBs respond to cardiac injury and disease, making them a key therapeutic target.
- Understanding the developmental origins of CFBs is essential for their therapeutic application.
Purpose of the Study:
- To investigate the impact of developmental lineage on the transcriptional and functional properties of human pluripotent stem cell-derived CFBs.
- To compare epicardial-derived CFBs (EpiC-FBs) and second heart field-derived CFBs (SHF-FBs).
- To determine the utility of different CFB subtypes in disease modeling and regenerative medicine.
Main Methods:
- Generation of CFBs from human pluripotent stem cells, differentiating into epicardial (EpiC-FB) and second heart field (SHF-FB) lineages.
- Transcriptional profiling to compare CFB subtypes.
- Functional assays assessing ECM composition, growth factor secretion, myofibroblast activation, and mineralization potential.
- Assessment of calcium handling in stem cell-derived cardiac tissues.
Main Results:
- Both EpiC-FBs and SHF-FBs exhibited cardiac fibroblast transcriptional programs and improved calcium handling in cardiac tissues.
- Significant differences were observed in ECM composition, growth factor secretion, and activation potential.
- EpiC-FBs showed higher stress-induced activation, resembling myofibroblasts.
- SHF-FBs demonstrated greater calcification and mineralization potential.
Conclusions:
- Developmental lineage significantly influences the phenotype and function of human pluripotent stem cell-derived CFBs.
- EpiC-FBs are suitable for modeling fibrotic heart diseases.
- SHF-FBs represent a promising cell source for cardiac regenerative therapies.
- This study provides insights into CFB regional and developmental specificity, informing the selection of in vitro models.
Abstract:
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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