Myofibroblast dedifferentiation proceeds via distinct transcriptomic and phenotypic transitions

Area of Science:

• Cell Biology
• Fibrosis Research
• Molecular Medicine

Background:

• Myofibroblasts drive tissue fibrosis through collagen production and resistance to cell death.
• Reversing fibrosis may involve myofibroblast dedifferentiation and restored apoptosis sensitivity.

Purpose of the Study:

• To comprehensively characterize and compare the distinct cellular phenotypes resulting from Prostaglandin E2 (PGE2) and FGF2-induced myofibroblast dedifferentiation.
• To elucidate the molecular pathways governing these dedifferentiation processes.

Main Methods:

• Human lung myofibroblasts were treated with PGE2 or FGF2.
• Cellular signaling pathways (cAMP/PKA and MEK/ERK) were investigated.
• Transcriptomic analysis was performed on resulting transitional cells.
• Gene expression patterns were compared to fibroblasts from mice with resolving experimental fibrosis.

Main Results:

• PGE2 induced myofibroblast dedifferentiation via cAMP/PKA, while FGF2 utilized MEK/ERK.
• Distinct transcriptomes were observed in transitional cells generated by PGE2 and FGF2.
• FGF2 promoted proliferation and survival, whereas PGE2 inhibited them.
• In vivo fibrosis resolution showed gene expression patterns similar to PGE2-treated myofibroblasts.

Conclusions:

• Myofibroblast dedifferentiation can occur through distinct molecular programs, exemplified by PGE2 and FGF2.
• The in vivo process of fibrosis resolution most closely mirrors the PGE2-induced dedifferentiation pathway.
• These findings suggest potential therapeutic avenues for fibrosis by targeting specific dedifferentiation mechanisms.