Mesenchymal Stem Cell Aggregation‐Released Extracellular Vesicles Induce CD31+EMCN+ Vessels in Skin Regeneration and Improve Diabetic Wound Healing

Author:

Liu Lu12,Zheng Chen‐Xi13,Zhao Na4,Zhu Ting156,Hu Cheng‐Biao4,Zhang Nan1,Chen Ji17,Zhang Kai‐Chao18,Zhang Sha19,Liu Jie‐Xi1,Zhang Kai110,Jing Huan11,Sui Bing‐Dong1,Jin Yan18ORCID,Jin Fang2

Affiliation:

1. 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

2. Department of Orthodontics School of Stomatology The Fourth Military Medical University Xi'an Shaanxi 710032 China

3. Department of Oral Histopathology School of Stomatology The Fourth Military Medical University Xi'an Shaanxi 710032 China

4. Xi'an Key Laboratory of Stem Cell and Regenerative Medicine Institute of Medical Research Northwestern Polytechnical University Xi'an Shaanxi 710072 China

5. Department of Preventive Dentistry School of Stomatology The Fourth Military Medical University Xi'an Shaanxi 710032 China

6. College of Life Science Northwest University Xi'an Shaanxi 710069 China

7. Department of Oral Implantology School of Stomatology The Fourth Military Medical University Xi'an Shaanxi 710032 China

8. Xi'an Institute of Tissue Engineering and Regenerative Medicine Xi'an Shaanxi 710032 China

9. Department of Traditional Chinese Medicine Xijing Hospital The Fourth Military Medical University Xi'an Shaanxi 710032 China

10. Department of Oral and Maxillofacial Surgery School of Stomatology The Fourth Military Medical University Xi'an Shaanxi 710032 China

11. Department of Endodontics Guangdong Provincial High‐level Clinical Key Specialty Guangdong Province Engineering Research Center of Oral Disease Diagnosis and Treatment Peking University Shenzhen Hospital Shenzhen Guangdong 518036 China

Abstract

AbstractThe 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.

Funder

National Natural Science Foundation of China

National Key Research and Development Program of China

Publisher

Wiley

Subject

Pharmaceutical Science,Biomedical Engineering,Biomaterials

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