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Extracellular Vesicles from Adipose-Derived Stem Cells Promote Diabetic Wound Healing via the PI3K-AKT-mTOR-HIF-1α Signaling Pathway

  • Original Article
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Tissue Engineering and Regenerative Medicine Aims and scope

Abstract

Background:

Impaired potential of hypoxia-mediated angiogenesis lead poor healing of diabetic wounds. Previous studies have shown that extracellular vesicles from adipose derived stem cells (ADSC-EVs) accelerate wound healing with unelucidated mechanism. However, it is not yet clear about the underlying mechanism of ADSC-EVs in regulating the hypoxia-related PI3K/AKT/mTOR signaling pathway of vascular endothelial cells in diabetic wounds. Therefore, in this study, human derived ADSC-EVs (hADSC-EVs) isolated from adipose tissue were co-cultured with advanced glycosylation end product (AGE) treated human umbilical vein endothelial cells (HUVECs) in vitro and local injected into the wounds of diabetic rats.

Methods:

In vitro, the therapeutic potential of hADSC-EVs on AGE-treated HUVECs was evaluated by cell counting kit-8, scratching, and tube formation assay. Subsequently, the effects of hADSC-EVs on the PI3K/AKT/mTOR/HIF-1α signaling pathway were also assayed by qRT-PCR and western blot. In vivo, the effect of hADSC-EVs on diabetic wound healing in rats were also assayed by closure kinetics, Masson staining and HIF-1α-CD31 immunofluorescence.

Results:

hADSC-EVs were spherical in shape with an average particle size of 198.1 ± 91.5 nm, and were positive for CD63, CD9 and TSG101. hADSC-EVs promoted the expression of PI3K-AKT-mTOR-HIF-1α signaling pathway of AGEs treated HUVECs with improved the potential of proliferation, migration and tube formation, and improve the healing and angiogenesis of diabetic wound in rats. However, the effect of hADSC-EVs described above can be blocked by PI3K-AKT inhibitor both in vitro and vivo.

Conclusion:

Our findings indicated that hADSC-EVs accolated the healing of diabetic wounds by promoting HIF-1α-mediated angiogenesis in the PI3K-AKT-mTOR depend manner.

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Acknowledgement

The present study was supported by the National Natural Science Foundation of China (Grant No. 81460293).

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Authors and Affiliations

  1. Institute of Burn, The First Affiliated Hospital of Nanchang University, Nanchang, 330006, People’s Republic of China

    Wenjian Liu, Yu Yuan & Dewu Liu

  2. Department of Burns and Plastics, JiangXi Provincial Corps Hospital of Chinese People’s Armed Police Forces, Nanchang, 330001, People’s Republic of China

    Wenjian Liu

  3. First Clinical Medical College, Nanchang University, Nanchang, 330006, People’s Republic of China

    Yu Yuan

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  1. Wenjian Liu
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Correspondence to Dewu Liu.

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The study was approved by the Medical Ethics Committee in the First Affiliated Hospital of Nanchang University (20140312) and written informed consents were obtained from participants.

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Liu, W., Yuan, Y. & Liu, D. Extracellular Vesicles from Adipose-Derived Stem Cells Promote Diabetic Wound Healing via the PI3K-AKT-mTOR-HIF-1α Signaling Pathway. Tissue Eng Regen Med 18, 1035–1044 (2021). https://doi.org/10.1007/s13770-021-00383-8

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  • DOI: https://doi.org/10.1007/s13770-021-00383-8

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