Exosomes derived from pioglitazone-pretreated MSCs accelerate diabetic wound healing through enhancing angiogenesis

J Nanobiotechnology. 2021 May 21;19(1):150. doi: 10.1186/s12951-021-00894-5.


Background: Enhanced angiogenesis can promote diabetic wound healing. Mesenchymal stem cells (MSCs)-derived exosomes, which are cell-free therapeutics, are promising candidates for the treatment of diabetic wound healing. The present study aimed to investigate the effect of exosomes derived from MSCs pretreated with pioglitazone (PGZ-Exos) on diabetic wound healing.

Results: We isolated PGZ-Exos from the supernatants of pioglitazone-treated BMSCs and found that PGZ-Exos significantly promote the cell viability and proliferation of Human Umbilical Vein Vascular Endothelial Cells (HUVECs) injured by high glucose (HG). PGZ-Exos enhanced the biological functions of HUVECs, including migration, tube formation, wound repair and VEGF expression in vitro. In addition, PGZ-Exos promoted the protein expression of p-AKT, p-PI3K and p-eNOS and suppressed that of PTEN. LY294002 inhibited the biological function of HUVECs through inhibition of the PI3K/AKT/eNOS pathway. In vivo modeling in diabetic rat wounds showed that pioglitazone pretreatment enhanced the therapeutic efficacy of MSCs-derived exosomes and accelerated diabetic wound healing via enhanced angiogenesis. In addition, PGZ-Exos promoted collagen deposition, ECM remodeling and VEGF and CD31 expression, indicating adequate angiogenesis in diabetic wound healing.

Conclusions: PGZ-Exos accelerated diabetic wound healing by promoting the angiogenic function of HUVECs through activation of the PI3K/AKT/eNOS pathway. This offers a promising novel cell-free therapy for treating diabetic wound healing.

Keywords: Angiogenesis; Diabetic wound; Exosomes; Mesenchymal stem cells; Pioglitazone.

MeSH terms

  • Angiogenesis Inducing Agents / pharmacology
  • Animals
  • Cell Movement / drug effects
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Collagen / metabolism
  • Diabetes Mellitus / metabolism*
  • Diabetes Mellitus, Experimental
  • Exosomes / metabolism*
  • Human Umbilical Vein Endothelial Cells / drug effects
  • Humans
  • Male
  • Mesenchymal Stem Cells / metabolism*
  • Phosphatidylinositol 3-Kinases / metabolism
  • Pioglitazone / metabolism*
  • Pioglitazone / pharmacology*
  • Rats
  • Rats, Sprague-Dawley
  • Skin / drug effects
  • Wound Healing / drug effects*


  • Angiogenesis Inducing Agents
  • Collagen
  • Pioglitazone