Comparison of the Therapeutic Effect of Allogeneic and Xenogeneic Small Extracellular Vesicles in Soft Tissue Repair

Abstract

Jia Dong,1– 3,* Yue Wu,1,2,4,* Yan Zhang,1– 3 Mei Yu,1,2 Weidong Tian1– 3 1State Key Laboratory of Oral Disease, Engineering Research Center of Oral Translational Medicine, Ministry of Education, West China School of Stomatology, Sichuan University, Chengdu, Sichuan, People’s Republic of China; 2National Engineering Laboratory for Oral Regenerative Medicine, Sichuan University, Chengdu, Sichuan, People’s Republic of China; 3Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, People’s Republic of China; 4Department of Oral & Maxillofacial Surgery, Xiangya Stomatological Hospital & School of Stomatology, Central South University, Changsha, Hunan, People’s Republic of China*These authors contributed equally to this workCorrespondence: Mei Yu; Weidong Tian State Key Laboratory of Oral Disease, West China School of StomatologySichuan University, No. 14, 3rd Sec., Ren Min Nan Road, Chengdu, Sichuan Province 610041, People’s Republic of ChinaTel/Fax [phone]Email [email protected]; [email protected]: Small extracellular vesicles (sEV) are a heterogeneous group of vesicles that consist of proteins, lipids and miRNA molecules derived from the cell of origin. Although xenogeneic sEV have been applied for soft tissue regeneration successfully, the regeneration effect of allogeneic and xenogeneic sEV has not been compared systematically.Methods: Our previous study has shown that sEV derived from rat adipose tissue successfully induced neoadipose regeneration. In this study, sEV were isolated from rat adipose tissue (r-sEV-AT) and porcine adipose tissue (p-sEV-AT), the morphology, size distribution and marker proteins expression of r-sEV-AT and p-sEV-AT were characterized. Besides, the sEV/AT ratio was evaluated and compared between r-sEV-AT and p-sEV-AT. Rat adipose-derived stromal/stem cells (rASCs) and rat aorta endothelial cells (rECs) were adopted to test the cellular response to allogeneic and xenogeneic sEV-AT. The effects of allogeneic and xenogeneic sEV-AT on host cells migration and neoadipose formation were evaluated in a subcutaneous custom-designed model. A full-thickness skin wound healing model was used to further compare the ability of allogeneic and xenogeneic sEV-AT in inducing complex soft tissue regeneration.Results: p-sEV-AT showed similar morphology and size distribution to r-sEV-AT. Marker proteins of sEV were detected in both r-sEV-AT and p-sEV-AT. The sEV/AT ratio of porcine was slightly higher than that of rat. The effects of r-sEV-AT and p-sEV-AT on the differentiation of rASCs and rECs showed no significant difference. When allogeneic and xenogeneic sEV-AT were subcutaneously implanted into the back of SD rats, the host cells chemotactic infiltration was observed in 1 week and neoadipose tissue formation was induced in 8 weeks; no significant difference was observed between allogeneic and xenogeneic sEV-AT. For complex soft tissue regeneration, both allogeneic and xenogeneic sEV-AT significantly promoted wound re-epithelialization, granulation tissue formation and hair follicle regeneration and then accelerated skin wound healing.Conclusion: Our results demonstrated that sEV derived from the same tissues of different species might be loaded with similar therapeutic substance benefitting tissue repair and regeneration, and paved the way for future research aimed at xenogeneic sEV application.Keywords: xenogeneic, small extracellular vesicles, neoadipose formation, skin wound repair

Keywords

• xenogeneic
• small extracellular vesicles
• neoadipose formation
• skin wound repair