Division of Pulmonary and Critical Care Medicine and.
BCRF Bioinformatics Core, University of Michigan, Ann Arbor, Michigan, USA.
JCI Insight. 2021 Mar 22;6(6):144799. doi: 10.1172/jci.insight.144799.
Myofibroblasts are the major cellular source of collagen, and their accumulation - via differentiation from fibroblasts and resistance to apoptosis - is a hallmark of tissue fibrosis. Clearance of myofibroblasts by dedifferentiation and restoration of apoptosis sensitivity has the potential to reverse fibrosis. Prostaglandin E2 (PGE2) and mitogens such as FGF2 have each been shown to dedifferentiate myofibroblasts, but - to our knowledge - the resultant cellular phenotypes have neither been comprehensively characterized or compared. Here, we show that PGE2 elicited dedifferentiation of human lung myofibroblasts via cAMP/PKA, while FGF2 utilized MEK/ERK. The 2 mediators yielded transitional cells with distinct transcriptomes, with FGF2 promoting but PGE2 inhibiting proliferation and survival. The gene expression pattern in fibroblasts isolated from the lungs of mice undergoing resolution of experimental fibrosis resembled that of myofibroblasts treated with PGE2 in vitro. We conclude that myofibroblast dedifferentiation can proceed via distinct programs exemplified by treatment with PGE2 and FGF2, with dedifferentiation occurring in vivo most closely resembling the former.
肌成纤维细胞是胶原的主要细胞来源，其通过从成纤维细胞分化和抵抗细胞凋亡而积累，是组织纤维化的标志。通过去分化和恢复细胞凋亡敏感性来清除肌成纤维细胞有可能逆转纤维化。已经证明前列腺素 E2 (PGE2) 和有丝分裂原如 FGF2 都可以使肌成纤维细胞去分化，但据我们所知，尚未对所得的细胞表型进行全面表征和比较。在这里，我们显示 PGE2 通过 cAMP/PKA 诱导人肺肌成纤维细胞去分化，而 FGF2 则利用 MEK/ERK。这两种介质产生了具有不同转录组的过渡细胞，FGF2 促进但 PGE2 抑制增殖和存活。从经历实验性纤维化消退的小鼠肺中分离出的成纤维细胞的基因表达模式与体外用 PGE2 处理的肌成纤维细胞相似。我们得出结论，肌成纤维细胞的去分化可以通过 PGE2 和 FGF2 治疗所示的不同程序进行，体内去分化最类似于前者。
