Developmental lineage of human pluripotent stem cell-derived cardiac fibroblasts affects their functional phenotype.
Developmental lineage of human pluripotent stem cell-derived cardiac fibroblasts affects their functional phenotype.
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人多能干细胞来源的心脏成纤维细胞的发育谱系影响其功能表型。
DOI：
10.1096/fj.202100523r
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发表时间：
2021-09
期刊：
影响因子：
--
通讯作者：
Palecek SP
中科院分区：
文献类型：
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作者：
Floy ME;Givens SE;Matthys OB;Mateyka TD;Kerr CM;Steinberg AB;Silva AC;Zhang J;Mei Y;Ogle BM;McDevitt TC;Kamp TJ;Palecek SP
心脏成纤维细胞(CFB)通过分泌细胞外基质(ECM)和旁分泌因子来支持心脏功能，对与损伤和疾病相关的应激做出反应，因此成为越来越重要的治疗靶点。我们描述了人类多能干细胞来源的CFB、心外膜(EPIC-FB)和第二心区(SHF-FB)的发育谱系如何影响转录和功能特性。EPIC-FBS和SHF-FBS都显示了CFB转录程序和改善了人类多能干细胞来源的心脏组织中的钙处理。我们鉴定了在合成的ECM的组成、生长和分化因子的分泌以及肌成纤维细胞激活潜能等方面的差异，EPIC-FBS表现出与肌成纤维细胞类似的更高的应激诱导激活潜能，而SHF-FBS表现出更高的钙化和矿化潜力。这些表型差异提示EPIC-FBS在模拟纤维化疾病方面有实用价值，而SHF-FBS是再生治疗的一个有前途的细胞来源。这项工作直接对比了CFB的区域和发育特异性，并为CFB体外模型的选择提供了依据。
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.