PTEN/PI3K/AKT pathway activation with hypoxia-induced human umbilical vein endothelial cell exosome for angiogenesis-based diabetic skin reconstruction
Z Y Li, Yuhao Bai, Hao Wu, Yisheng Feng, Xinxi Wang, Xinxi Wang, Cancan Zhao, Xudong Wang, Xudong Wang
Abstract
Diabetic skin, a major clinical challenge due to impaired wound healing, is often exacerbated by a hypoxic microenvironment at the wound site. Exosomes have been proven to have excellent biological activities and applied to solve many bioengineering problems. However, the wide application of exosomes is still limited by their short in vitro lifetime and low yield. To overcome these application limitations, this study specifically enhances the pro-angiogenic biological efficacy of exosomes through hypoxic treatment and achieves sustained release using hydrogel loading. In vitro, hypoxia-induced exosomes (Hp-Exo) significantly enhanced endothelial cell migration, proliferation, and angiogenic capacity. In vivo, Gelman hydrogels loaded with Hp-Exo accelerated wound closure, promoted collagen deposition, and increased vascularization in diabetic mice. miRNA sequencing of Hp-Exo revealed that exosomes induced under hypoxic conditions contain various miRNAs, which enhance vascular endothelial cell proliferation, migration, and angiogenesis through the PTEN/PI3K/AKT pathway. These results highlight that hypoxia-induced exosomes, when delivered through a biocompatible hydrogel platform, provide potential therapeutic approach to improve diabetic wound healing by stimulating angiogenesis and tissue regeneration. Hypoxia-induced exosomes exhibit pro-angiogenic potential. Sustained release was achieved through hydrogel loading, and hypoxia-induced exosomes (Hp-Exo) enhanced endothelial cell functions in vitro, accelerating wound healing and vascular formation in diabetic mice. miRNA analysis indicated that Hp-Exo promote angiogenesis via the PTEN/PI3K/AKT pathway, offering a promising approach for improving diabetic wound healing. • Hypoxia-induced exosomes exhibit pro-angiogenic potential. • The HUVEC cell line as the source of exosomes ensures the stability of exosome biofunction. • Sustained exosome release was achieved through hydrogel loading • Hp-Exo promote angiogenesis via the PTEN/PI3K/AKT pathway