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Theranostics 2018; 8(6):1607-1623. doi:10.7150/thno.22958 This issue Cite

Research Paper

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

Chun-Yuan Chen^1*, Shan-Shan Rao^1,5*, Lu Ren⁶, Xiong-Ke Hu¹, Yi-Juan Tan¹, Yin Hu^1,4, Juan Luo¹, Yi-Wei Liu^1,3, Hao Yin^1,4, Jie Huang^1,4, Jia Cao¹, Zhen-Xing Wang¹, Zheng-Zhao Liu¹, Hao-Ming Liu¹, Si-Yuan Tang⁶, Ran Xu⁷, Hui Xie^1,2,3,4,8✉

1. Movement System Injury and Repair Research Center, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China.
2. Hunan Key Laboratory of Organ Injury, Aging and Regenerative Medicine, Changsha, Hunan, China.
3. Department of Sports Medicine, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China.
4. Department of Orthopedics, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China.
5. Department of Spine Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China.
6. Xiangya Nursing School, Central South University, Changsha, Hunan 410013, China
7. Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China
8. China Orthopedic Regenerative Medicine Group (CORMed), Changsha, Hunan, China.
* Chun-Yuan Chen and Shan-Shan Rao contributed equally to this work.

✉ Corresponding author: Hui Xie: huixieedu.cn; #88 Xiangya Road, Changsha, 410008, PR China; Tel: 86-0731-84327068

Abstract

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.

Keywords: exosomes, urine-derived stem cells, chronic wound, angiogenesis, DMBT1

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