FOSL1-mediated super-enhancer facilitates pathological scarring

Area of Science:

• Dermatology
• Molecular Biology
• Wound Healing Research

Background:

• Pathological scarring, marked by excessive fibrosis, results from abnormal wound healing.
• The molecular drivers of scar formation are not fully understood.
• Identifying these drivers is crucial for developing effective treatments.

Purpose of the Study:

• To identify molecular factors contributing to hypertrophic scars and keloids.
• To elucidate the mechanism by which these factors promote fibrosis.
• To evaluate a potential therapeutic intervention targeting these factors.

Main Methods:

• Single-cell RNA sequencing (scRNA-seq) was employed to analyze cell populations in scar tissue.
• Investigated the role of FOSL1 (a transcription factor) and MMP3 (a matrix metalloproteinase) in fibrosis.
• Utilized in vivo xenogenic keloid models to test a FOSL1 inhibitor (SR11302).

Main Results:

• Identified FOSL1-expressing keratinocytes that are expanded in hypertrophic scars and keloids.
• These FOSL1+ keratinocytes exhibit epithelial-mesenchymal transition (EMT) and secrete MMP3, activating fibroblasts.
• FOSL1 directly upregulates MMP3 transcription via a MED-1 super-enhancer, promoting inflammation and fibrosis.
• SR11302 treatment significantly reduced scar formation in preclinical models.

Conclusions:

• Aberrant FOSL1+ keratinocytes and their MMP3 secretion are key drivers of pathological scarring.
• Targeting FOSL1 represents a promising therapeutic strategy for managing excessive fibrosis and improving wound healing.
• This research provides a foundation for developing interventions aimed at achieving scarless healing.