Exosomal DMBT1 from human urine-derived stem cells facilitates diabetic wound repair by promoting angiogenesis

被引：368

作者：

Chen, Chun-Yuan ^{[1
]}

Rao, Shan-Shan ^{[1
,5
]}

Ren, Lu ^{[6
]}

Hu, Xiong-Ke ^{[1
]}

Tan, Yi-Juan ^{[1
]}

Hu, Yin ^{[1
,4
]}

Luo, Juan ^{[1
]}

Liu, Yi-Wei ^{[1
,3
]}

Yin, Hao ^{[1
,4
]}

Huang, Jie ^{[1
,4
]}

Cao, Jia ^{[1
]}

Wang, Zhen-Xing ^{[1
]}

Liu, Zheng-Zhao ^{[1
]}

Liu, Hao-Ming ^{[1
]}

Tang, Si-Yuan ^{[6
]}

Xu, Ran ^{[7
]}

Xie, Hui ^{[1
,2
,3
,4
,8
]}

机构：

[1] Cent S Univ, Xiangya Hosp, Movement Syst Injury & Repair Res Ctr, Changsha 410008, Hunan, Peoples R China

[2] Hunan Key Lab Organ Injury Aging & Regenerat Med, Changsha, Hunan, Peoples R China

[3] Cent S Univ, Xiangya Hosp, Dept Sports Med, Changsha 410008, Hunan, Peoples R China

[4] Cent S Univ, Xiangya Hosp, Dept Orthoped, Changsha 410008, Hunan, Peoples R China

[5] Cent S Univ, Xiangya Hosp, Dept Spine Surg, Changsha 410008, Hunan, Peoples R China

[6] Cent S Univ, Xiangya Nursing Sch, Changsha 410013, Hunan, Peoples R China

[7] Cent S Univ, Xiangya Hosp 2, Changsha 410011, Hunan, Peoples R China

[8] China Orthoped Regenerat Med Grp CORMed, Changsha, Hunan, Peoples R China

来源：

THERANOSTICS | 2018年 / 8卷 / 06期

基金：

中国博士后科学基金; 中国国家自然科学基金;

关键词：

exosomes; urine-derived stem cells; chronic wound; angiogenesis; DMBT1; BRAIN-TUMORS; 1; EXTRACELLULAR-MATRIX; REGENERATIVE MEDICINE; GROWTH-FACTORS; CANCER; DIFFERENTIATION; OSTEOGENESIS; FIBROBLASTS; EXPRESSION; ISCHEMIA;

D O I：

10.7150/thno.22958

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

100103 [病原生物学]; 100218 [急诊医学];

摘要：

Chronic non-healing wounds represent one of the most common complications of diabetes and need advanced treatment strategies. Exosomes are key mediators of cell paracrine action and can be directly utilized as therapeutic agents for tissue repair and regeneration. Here, we explored the effects of exosomes from human urine-derived stem cells (USC-Exos) on diabetic wound healing and the underlying mechanism. Methods: USCs were characterized by flow cytometry and multipotent differentiation potential analyses. USC-Exos were isolated from the conditioned media of USCs and identified by transmission electron microscopy and flow cytometry. A series of functional assays in vitro were performed to assess the effects of USC-Exos on the activities of wound healing-related cells. Protein profiles in USC-Exos and USCs were examined to screen the candidate molecules that mediate USC-Exos function. The effects of USC-Exos on wound healing in streptozotocin-induced diabetic mice were tested by measuring wound closure rates, histological and immunofluorescence analyses. Meanwhile, the role of the candidate protein in USC-Exos-induced regulation of angiogenic activities of endothelial cells and diabetic wound healing was assessed. Results: USCs were positive for CD29, CD44, CD73 and CD90, but negative for CD34 and CD45. USCs were able to differentiate into osteoblasts, adipocytes and chondrocytes. USC-Exos exhibited a cup-or sphere-shaped morphology with a mean diameter of 51.57 +/- 2.93 nm and positive for CD63 and TSG101. USC-Exos could augment the functional properties of wound healing-related cells including the angiogenic activities of endothelial cells. USC-Exos were enriched in the proteins that are involved in regulation of wound healing-related biological processes. Particularly, a pro-angiogenic protein called deleted in malignant brain tumors 1 (DMBT1) was highly expressed in USC-Exos. Further functional assays showed that DMBT1 protein was required for USC-Exos-induced promotion of angiogenic responses of cultured endothelial cells, as well as angiogenesis and wound healing in diabetic mice. Conclusion: Our findings suggest that USC-Exos may represent a promising strategy for diabetic soft tissue wound healing by promoting angiogenesis via transferring DMBT1 protein.

引用

页码：1607 / 1623

页数：17

共 51 条

[1]

Priming with proangiogenic growth factors and endothelial progenitor cells improves revascularization in linear diabetic wounds [J].