GelMA hydrogel-loaded extracellular vesicles derived from keratinocytes promote skin microvasculature regeneration and wound healing in diabetic mice through activation of the PDGF-induced PI3K/AKT pathway

Area of Science:

• Biomaterials Science
• Regenerative Medicine
• Wound Healing Research

Background:

• Diabetic skin ulcers present a significant clinical challenge due to impaired wound healing.
• Extracellular vesicles (EVs) are emerging as key mediators in cellular communication and tissue repair.

Purpose of the Study:

• To investigate the efficacy of keratinocyte-derived EVs cultured in Gelatin Methacryloyl (GelMA) hydrogels for promoting microvascular regeneration and healing diabetic skin ulcers.
• To elucidate the underlying molecular mechanisms, including growth factor signaling pathways.

Main Methods:

• Harvesting and characterization of EVs from keratinocyte cultures within GelMA hydrogels.
• Assessing EV angiogenic effects on human umbilical vein endothelial cells (HUVECs) and performing transcriptomic profiling.
• Establishing and validating a diabetic murine wound model for in vivo evaluation.

Main Results:

• Keratinocyte-derived EVs significantly enhanced HUVEC proliferation, migration, and tube formation.
• In vivo studies demonstrated accelerated wound closure, improved re-epithelialization, vascularization, and collagen deposition in diabetic mice treated with GelMA-EVs.
• Elevated Platelet-Derived Growth Factor (PDGF) expression and activation of the PI3K/AKT pathway were identified as key mechanisms.

Conclusions:

• GelMA hydrogel-loaded keratinocyte EVs effectively promote microvascular reconstruction and accelerate wound healing in diabetic skin ulcers.
• Upregulation of PDGF and activation of the PI3K/AKT pathway are critical for the therapeutic effects of these EVs.