Topical Application of Tat-Rac1 Promotes Cutaneous Wound Healing in Normal and Diabetic Mice

Area of Science:

• Biochemistry
• Dermatology
• Regenerative Medicine

Background:

• Endogenous Rac1 (Ras-related C3 botulinum toxin substrate 1) is crucial for normal skin wound healing.
• The role and activation of Rac1 in chronic wounds, particularly diabetic wounds, remain unclear.
• Investigating therapeutic potential of exogenous Rac1 in wound healing is warranted.

Purpose of the Study:

• To determine if endogenous Rac1 is adequately activated in chronic diabetic wounds.
• To evaluate the therapeutic efficacy of exogenous Rac1 in promoting wound healing.

Main Methods:

• Compared Rac1 protein levels in wounds of diabetic (db/db) and wild-type mice.
• Developed Tat-Rac1 fusion protein for cellular delivery via protein transduction.
• Assessed Tat-Rac1 effects on keratinocyte and fibroblast proliferation and migration in vitro.
• Evaluated topical Tat-Rac1 application on wound closure, re-epithelialization, and inflammation in vivo.

Main Results:

• Rac1 protein levels were significantly lower in db/db diabetic mouse wounds compared to wild-type.
• Tat-Rac1 enhanced keratinocyte and dermal fibroblast proliferation and migration in vitro.
• Topical Tat-Rac1 accelerated wound closure in both db/db and wild-type mice.
• Tat-Rac1 promoted faster re-epithelialization, increased keratinocyte proliferation/migration, and reduced inflammation without accelerating myofibroblast activation.

Conclusions:

• Diabetic wounds exhibit a failure to adequately increase Rac1 expression during the healing process.
• Exogenous Tat-Rac1 demonstrates therapeutic potential by compensating for Rac1 deficiency.
• Rac1-based biologics offer a promising strategy for enhancing chronic wound healing.