International Journal of Nanomedicine (Nov 2023)

ApoSEVs-Mediated Modulation of Versatile Target Cells Promotes Diabetic Wound Healing: Unveiling a Promising Strategy

  • Yang J,
  • Zhang X,
  • Wang G,
  • Ma S,
  • Yu Y,
  • Liao C,
  • Wang Z,
  • Liang C,
  • Li M,
  • Tian W,
  • Liao L

Journal volume & issue
Vol. Volume 18
pp. 6955 – 6977

Abstract

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Jian Yang,1,* Xuanhao Zhang,1,2,* Guanyu Wang,1,2 Shixing Ma,1,2 Yejia Yu,1 Chengcheng Liao,1 Zhuo Wang,1,2 Cheng Liang,1 Maojiao Li,1,2 Weidong Tian,1,2 Li Liao1,2 1State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases & Engineering Research Center of Oral Translational Medicine, Ministry of Education & National Engineering Laboratory for Oral Regenerative Medicine, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, People’s Republic of China; 2Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, People’s Republic of China*These authors contributed equally to this workCorrespondence: Li Liao; Weidong Tian, State Key Laboratory of Oral Disease, West China School of Stomatology, Sichuan University, No. 14, 3Rd Section of Ren Min Nan Road, Chengdu, Sichuan, 610041, People’s Republic of China, Tel +86-28-85503499 ; +86-28-85501256, Email [email protected]; [email protected]: Diabetic chronic wounds present a formidable challenge in clinical management, lacking effective treatment options. Mesenchymal stem cell (MSC) transplantation has emerged as a promising therapy for tissue repair and regeneration. However, transplanted MSCs often undergo rapid apoptosis, giving rise to heterogeneous extracellular vesicles (EVs), including apoptotic bodies (apoBDs) and apoptotic small extracellular vesicles (apoSEVs). The potential stimulatory role of these EVs in diabetic wound healing remains unknown.Methods: In this study, we investigated the effects of apoSEVs derived from adipose-derived mesenchymal/stromal cells (ADSCs) on the recovery of diabetic wounds by modulating the function of versatile target cells. First, we characterized the apoSEVs and apoBDs derived from apoptotic ADSCs. Subsequently, we evaluated the effects of apoSEVs and apoBDs on macrophages, endothelial cells, and fibroblasts, three essential cell types in wound healing, under high-glucose conditions. Furthermore, we developed a gelatin methacryloyl (GelMA) hydrogel for the sustained release of apoSEVs and investigated its therapeutic effects on wound healing in type 2 diabetic mice in vivo.Results: apoSEVs facilitated the polarization of M1 phenotype macrophages to M2 phenotype, promoted proliferation, migration, and tube formation of endothelial cells, and enhanced fibroblast proliferation and migration. However, apoBDs failed to improve the function of endothelial cells and fibroblasts. In vivo, the apoSEVs-loaded GelMA effectively promoted wound healing by facilitating collagen fiber deposition, angiogenesis, and immune regulation.Conclusion: Our study elucidates the beneficial effects of apoSEVs on wound recovery in diabetes and introduces a novel strategy for diabetic wound treatment based on apoSEVs. Keywords: apoptotic small extracellular vesicles, wound healing, diabetes, stem cells, GelMA

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