Identification of Skin Multicellular Reprogramming Factors as Potential Treatment for Nonhealing Diabetic Foot Ulcers

Area of Science:

• Biomedical research
• Molecular biology
• Regenerative medicine

Background:

• Diabetic foot ulcers (DFU) present a complex wound healing challenge.
• Multiple cell types and their interactions influence DFU progression.
• Identifying key regulators of cell state is crucial for therapeutic development.

Purpose of the Study:

• To identify a transcription factor (TF) cocktail that can induce a transition from nonhealing to healing states in DFU.
• To analyze the activity of cell type-specific TFs in healing versus nonhealing DFU.
• To assess the cumulative additive effect of different TF cocktails.

Main Methods:

• Single-cell RNA sequencing analysis of 33 DFU skin and wound samples (85,928 cells).
• Comparative analysis of TF activity in healing versus nonhealing DFU.
• Computational assessment of TF cocktail effects, including in silico knockouts.

Main Results:

• A five-TF cocktail (FOSL2, CREB3L1, RELB, ETS1, XBP1) targets key pro-healing genes across cell types.
• This TF panel significantly regulates vasculature development and antimicrobial response genes in specific cell types.
• In silico TF knockouts demonstrated the panel's ability to shift cell states towards healing.

Conclusions:

• A novel TF cocktail has been identified with potential therapeutic value for nonhealing DFU.
• This TF cocktail can reprogram DFU cell states, promoting a switch to healing outcomes.
• The findings provide a blueprint for targeted regenerative therapies for DFU.