Purpose: 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


中文翻译：

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同种异体和异种细胞外小囊泡在软组织修复中的治疗效果比较

目的：小细胞外囊泡 (sEV) 是一组异质的囊泡，由源自细胞的蛋白质、脂质和 miRNA 分子组成。尽管异种sEV已成功应用于软组织再生，但尚未系统比较异种sEV和异种sEV的再生效果。
方法：我们之前的研究表明，源自大鼠脂肪组织的 sEV 成功地诱导了新脂肪再生。本研究从大鼠脂肪组织 (r-sEV-AT) 和猪脂肪组织 (p-sEV-AT) 中分离出 sEV，r-sEV-AT 和 p-sEV-AT 的形态、大小分布和标记蛋白表达AT进行了表征。此外，评估和比较了 r-sEV-AT 和 p-sEV-AT 之间的 sEV/AT 比率。采用大鼠脂肪来源的基质/干细胞 (rASCs) 和大鼠主动脉内皮细胞 (rECs) 来测试细胞对同种异体和异种 sEV-AT 的反应。在皮下定制设计的模型中评估了同种异体和异种 sEV-AT 对宿主细胞迁移和新脂肪形成的影响。
结果：p-sEV-AT 表现出与 r-sEV-AT 相似的形态和尺寸分布。在 r-sEV-AT 和 p-sEV-AT 中都检测到了 sEV 的标记蛋白。猪的sEV/AT比略高于大鼠。r-sEV-AT 和 p-sEV-AT 对 rASCs 和 rECs 分化的影响没有显着差异。SD大鼠背部皮下植入同种异体sEV-AT，1周后观察到宿主细胞趋化浸润，8周后诱导新脂肪组织形成；在同种异体和异种 sEV-AT 之间没有观察到显着差异。对于复杂的软组织再生，同种异体和异种sEV-AT均能显着促进伤口上皮再生、肉芽组织形成和毛囊再生，进而加速皮肤伤口愈合。
结论：我们的研究结果表明，来自不同物种的相同组织的 sEV 可能负载有相似的治疗物质，有利于组织修复和再生，并为未来针对异种 sEV 应用的研究铺平了道路。

关键词：异种，细胞外小囊泡，新脂肪形成，皮肤伤口修复