State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, School of Stomatology, The Fourth Military Medical University, Xi'an, Shaanxi, 710032, China.
Department of Orthodontics, School of Stomatology, The Fourth Military Medical University, Xi'an, Shaanxi, 710032, China.
Adv Healthc Mater. 2023 Aug;12(20):e2300019. doi: 10.1002/adhm.202300019. Epub 2023 Apr 20.
The blood vessel system is essential for skin homeostasis and regeneration. While the heterogeneity of vascular endothelial cells has been emergingly revealed, whether a regeneration-relevant vessel subtype exists in skin remains unknown. Herein, a specialized vasculature in skin featured by simultaneous CD31 and EMCN expression contributing to the regeneration process is identified, the decline of which functionally underlies the impaired angiogenesis of diabetic nonhealing wounds. Moreover, enlightened by the developmental process that mesenchymal condensation induces angiogenesis, it is demonstrated that mesenchymal stem/stromal cell aggregates (CAs) provide an efficacious therapy to enhance regrowth of CD31 EMCN vessels in diabetic wounds, which is surprisingly suppressed by pharmacological inhibition of extracellular vesicle (EV) release. It is further shown that CAs promote secretion of angiogenic protein-enriched EVs by proteomic analysis, which directly exert high efficacy in boosting CD31 EMCN vessels and treating nonhealing diabetic wounds. These results add to the current knowledge on skin vasculature and help establish feasible strategies to benefit wound healing under diabetic condition.
血管系统对于皮肤的稳态和再生至关重要。虽然血管内皮细胞的异质性已经逐渐显现，但皮肤中是否存在与再生相关的血管亚型尚不清楚。本文鉴定出一种在皮肤中具有特征性的特殊血管，其特征是同时表达 CD31 和 EMCN，有助于再生过程，其功能下降是糖尿病难愈合伤口血管生成受损的基础。此外，受间充质凝聚诱导血管生成的发育过程启发，本文证明间充质干细胞/基质细胞聚集物（CAs）通过抑制细胞外囊泡（EV）释放提供了一种有效的治疗方法，可增强糖尿病伤口中 CD31 EMCN 血管的再生，但令人惊讶的是，该方法被 EV 释放的药理学抑制所抑制。进一步的蛋白质组学分析表明，CAs 促进富含血管生成蛋白的 EV 的分泌，这些 EV 可直接高效促进 CD31 EMCN 血管的生成，并治疗糖尿病难愈合伤口。这些结果增加了对皮肤血管系统的现有认识，并有助于建立在糖尿病条件下有益于伤口愈合的可行策略。
