Human mesenchymal stromal cell-derived extracellular vesicles alleviate renal ischemic reperfusion injury and enhance angiogenesis in rats.
BACKGROUND
Mesenchymal stromal cells (MSCs) derived extracellular vesicles (EVs) were regarded as a potent medium for kidney injury repair and angiogenesis were regarded as an important step in tissue regeneration. However, the pro-angiogenesis effect of MSC-EVs in ischemia-reperfusion induced kidney injury and its potential mechanisms have yet to be determined.


METHODS
EVs were isolated from the medium of human umbilical cord-derived MSCs (huMSCs) were injected in rats intravenously after unilateral kidney ischemia. Animals were sacrificed at 24 h and 2 weeks after injury. The renal functions and histology staining were examined to assess the therapeutic effect of the EVs. Moreover, we investigated the pro-angiogenesis effects of EVs in injured kidneys and tested the angiogenesis-related factors to further illuminate the probable mechanisms.


RESULTS
It was observed that EVs could reduce cell apoptosis and enhances proliferation 24 h after kidney injury, meanwhile renal function was improved and the histological lesion was mitigated. Moreover, renal VEGF was up-regulated by EVs and HIF-1α was down-regulated. Further, the increase of capillary vessel density and reduce of renal fibrosis was observed after 2 weeks. Invitro, EVs could deliver human VEGF directly to renal tubular epithelial cells (TECs) and increase VEGF levels. Most important, all the beneficial effects of EVs were abrogated by RNase treated except for the delivery of human VEGF.


CONCLUSIONS
Human MSC-EVs could protect against ischemic/reperfusion injury induced kidney injury through pro-angiogenesis effects in HIF-1α independent manner, and both the delivery of pro-angiogenesis related VEGF and RNAs were involved in this process.
Department of Urology, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong UniversityShanghai, China; Department of Urology, Shanghai First People's Hospital, School of Medicine, Shanghai Jiao Tong UniversityShanghai, China.
Xiangyu
X
Zou
Department of Urology, Shanghai First People's Hospital, School of Medicine, Shanghai Jiao Tong University Shanghai, China.
Di
D
Gu
Department of Urology, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University Shanghai, China.
Xiaoyu
X
Xing
Department of Urology, Ningbo No.2 Hospital Ningbo, China.
Zhongliang
Z
Cheng
Department of Urology, Shanghai First People's Hospital, School of Medicine, Shanghai Jiao Tong University Shanghai, China.
Dongliang
D
Gong
Department of Urology, Shanghai First People's Hospital, School of Medicine, Shanghai Jiao Tong UniversityShanghai, China; Department of Urology, Affiliated Zhongda Hospital of Southeast UniversityNanjing, China.
Guangyuan
G
Zhang
Department of Urology, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University Shanghai, China.
Yingjian
Y
Zhu
AKI; CKD; Mesenchymal stromal cells; angiogenesis; extracellular vesicles