Myofibroblast dedifferentiation proceeds via distinct transcriptomic and phenotypic transitions

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 E-2 (PGE(2)) 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 PGE(2) 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 PGE(2) 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 PGE(2) in vitro. We conclude that myofibroblast dedifferentiation can proceed via distinct programs exemplified by treatment with PGE(2) and FGF2, with dedifferentiation occurring in vivo most closely resembling the former.

Automated summary

Myofibroblast dedifferentiation can be achieved through distinct programs, with PGE(2) and FGF2 treatments resulting in transitional cells with different transcriptomes, where the former is more similar to in vivo dedifferentiation.