Dendritic Cell-Associated MARCKSL1 Regulates Fibroblast Differentiation During Wound Healing

Area of Science:

• Regenerative Medicine
• Immunology
• Dermatology

Background:

• Immune cells, particularly dendritic cells, are crucial in wound healing and scar formation.
• Dendritic cells' role extends beyond antigen presentation to modulating fibrotic processes.
• Identifying specific molecular pathways in dendritic cells involved in scarring is key for therapeutic development.

Purpose of the Study:

• To investigate the role of myristoylated alanine-rich C-kinase substrate-like 1 (MARCKSL1) in dendritic cells during wound healing and scar formation.
• To determine if MARCKSL1 expression in dendritic cells influences fibroblast activity.
• To evaluate the therapeutic potential of targeting MARCKSL1 in dendritic cells for scar prevention.

Main Methods:

• Single-cell RNA sequencing of murine scar tissue to identify MARCKSL1 expression in dendritic cells.
• Utilizing a mouse fetal wound healing model to observe MARCKSL1-positive dendritic cell accumulation.
• Stimulating mouse dendritic cells with transforming growth factor beta 1 (TGF-β1) and co-culturing with fibroblasts.
• Employing MARCKSL1 shRNA to knockdown expression in dendritic cells and MANS peptide as an inhibitor in vivo.

Main Results:

• MARCKSL1 was identified in dendritic cell clusters within fibrotic regions of murine scars.
• MARCKSL1-positive dendritic cells accumulated at wound margins during scar formation.
• TGF-β1 stimulation enhanced MARCKSL1 expression in dendritic cells, promoting fibroblast to myofibroblast differentiation.
• MARCKSL1 knockdown in dendritic cells diminished this pro-fibrotic effect.
• Inhibition of MARCKSL1 with MANS peptide significantly reduced scar formation in mice.

Conclusions:

• MARCKSL1 expression in dendritic cells plays a significant role in modulating fibroblast activity and promoting fibrotic responses during wound healing.
• Targeting MARCKSL1 in dendritic cells represents a promising therapeutic strategy for preventing excessive scarring and promoting regenerative wound healing.