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Objective <p>This study explores how extracellular vesicles (EVs) derived from keratinocytes cultured in Gelatin Methacryloyl (GelMA) hydrogels facilitate microvascular regeneration and enhance wound repair in diabetic skin ulcers.</p> Methods <p>EVs were harvested from keratinocyte cultures via ultracentrifugation and ultrafiltration, followed by characterization. Their uptake and angiogenic effects on human umbilical vein endothelial cells (HUVECs) were assessed in the following experimentations. Transcriptomic profiling of EV-treated HUVECs identified angiogenesis-related gene expression changes. A diabetic murine wound model was established and validated via glycemic profiling and pancreatic histology. In vivo effects of GelMA-EVs were evaluated through wound closure rates, histology (re-epithelialization, vascularization, collagen deposition), CD31 staining, and microvascular imaging.</p> Results <p>Keratinocyte-derived EVs significantly enhanced HUVEC proliferation, migration, and tube formation. Mechanistic studies reported elevated PDGF expression, activating the PI3K/AKT pathway. In vivo experiments validated that GelMA hydrogel-loaded EVs increased PDGF expression in wound tissues, promoting microvascular reconstruction and accelerating wound healing in diabetic mouse skin ulcers.</p> Conclusion <p>GelMA hydrogel-loaded EVs derived from keratinocytes upregulate PDGF, activating the PI3K/AKT pathway to promote microvascular network reconstruction and enhance wound healing in diabetic mouse skin ulcers.</p> Graphical Abstract <p>Graphical Highlight<UnorderedList Mark="None"> <ItemContent> <p>Keratinocyte-derived EVs were loaded into GelMA hydrogel for sustained release.</p> </ItemContent> <ItemContent> <p>GelMA-EVs significantly enhanced endothelial proliferation, migration, and tube formation.</p> </ItemContent> <ItemContent> <p>In vivo, GelMA-EVs accelerated diabetic wound healing and microvascular reconstruction.</p> </ItemContent> <ItemContent> <p>Mechanistically, EVs activated the PDGF/PI3K/AKT pathway to mediate regeneration.</p> </ItemContent> </UnorderedList></p> <p></p>

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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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年6月14日

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  • Qian Li,
  • Leilei Zhou,
  • Wenqiang Li,
  • Weiheng Zhao,
  • Weimin Chen,
  • Mohammed S. AlQranei,
  • Jiarui Bi,
  • Ping Huang

摘要

Objective

This study explores how extracellular vesicles (EVs) derived from keratinocytes cultured in Gelatin Methacryloyl (GelMA) hydrogels facilitate microvascular regeneration and enhance wound repair in diabetic skin ulcers.

Methods

EVs were harvested from keratinocyte cultures via ultracentrifugation and ultrafiltration, followed by characterization. Their uptake and angiogenic effects on human umbilical vein endothelial cells (HUVECs) were assessed in the following experimentations. Transcriptomic profiling of EV-treated HUVECs identified angiogenesis-related gene expression changes. A diabetic murine wound model was established and validated via glycemic profiling and pancreatic histology. In vivo effects of GelMA-EVs were evaluated through wound closure rates, histology (re-epithelialization, vascularization, collagen deposition), CD31 staining, and microvascular imaging.

Results

Keratinocyte-derived EVs significantly enhanced HUVEC proliferation, migration, and tube formation. Mechanistic studies reported elevated PDGF expression, activating the PI3K/AKT pathway. In vivo experiments validated that GelMA hydrogel-loaded EVs increased PDGF expression in wound tissues, promoting microvascular reconstruction and accelerating wound healing in diabetic mouse skin ulcers.

Conclusion

GelMA hydrogel-loaded EVs derived from keratinocytes upregulate PDGF, activating the PI3K/AKT pathway to promote microvascular network reconstruction and enhance wound healing in diabetic mouse skin ulcers.

Graphical Abstract

Graphical Highlight

Keratinocyte-derived EVs were loaded into GelMA hydrogel for sustained release.

GelMA-EVs significantly enhanced endothelial proliferation, migration, and tube formation.

In vivo, GelMA-EVs accelerated diabetic wound healing and microvascular reconstruction.

Mechanistically, EVs activated the PDGF/PI3K/AKT pathway to mediate regeneration.