Exosomal miR-125b-5p deriving from mesenchymal stem cells promotes tubular repair by suppression of p53 in ischemic acute kidney injury

被引：315

作者：

Cao, Jing-Yuan ^{[1
]}

Wang, Bin ^{[1
]}

Tang, Tao-Tao ^{[1
]}

Wen, Yi ^{[1
]}

Li, Zuo-Lin ^{[1
]}

Feng, Song-Tao ^{[1
]}

Wu, Min ^{[1
]}

Liu, Dan ^{[1
]}

Yin, Di ^{[1
]}

Ma, Kun-Ling ^{[1
]}

Tang, Ri-Ning ^{[1
]}

Wu, Qiu-Li ^{[1
]}

Lan, Hui-Yao ^{[2
]}

Lv, Lin-Li ^{[1
]}

Liu, Bi-Cheng ^{[1
]}

机构：

[1] Southeast Univ, Zhong Da Hosp, Inst Nephrol, Sch Med, 87 Ding Jia Qiao Rd, Nanjing 210009, Jiangsu, Peoples R China

[2] Chinese Univ Hong Kong, Li Ka Shing Inst Hlth Sci, Liu Che Woo Inst Innovat Med, Dept Med & Therapeut, Hong Kong 999077, Peoples R China

来源：

THERANOSTICS | 2021年 / 11卷 / 11期

基金：

中国国家自然科学基金;

关键词：

mesenchymal stem cell; exosomes; miR-125b-5p; tubular repair; acute kidney injury; HUMAN UMBILICAL-CORD; EXTRACELLULAR VESICLES; BONE-MARROW; MECHANISMS; SENESCENCE; CHALLENGES; BIOMARKERS; DELIVERY; DISEASE; CULTURE;

D O I：

10.7150/thno.54550

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：

Mesenchymal stem cells-derived exosomes (MSC-exos) have attracted great interest as a cell-free therapy for acute kidney injury (AKI). However, the in vivo biodistribution of MSC-exos in ischemic AKI has not been established. The potential of MSC-exos in promoting tubular repair and the underlying mechanisms remain largely unknown. Methods: Transmission electron microscopy, nanoparticle tracking analysis, and western blotting were used to characterize the properties of human umbilical cord mesenchymal stem cells (hucMSCs) derived exosomes. The biodistribution of MSC-exos in murine ischemia/reperfusion (I/R) induced AKI was imaged by the IVIS spectrum imaging system. The therapeutic efficacy of MSC-exos was investigated in renal I/R injury. The cell cycle arrest, proliferation and apoptosis of tubular epithelial cells (TECs) were evaluated in vivo and in HK-2 cells. The exosomal miRNAs of MSC-exos were profiled by high-throughput miRNA sequencing. One of the most enriched miRNA in MSC-exos was knockdown by transfecting miRNA inhibitor to hucMSCs. Then we investigated whether this candidate miRNA was involved in MSC-exos-mediated tubular repair. Results: Ex vivo imaging showed that MSC-exos was efficiently homing to the ischemic kidney and predominantly accumulated in proximal tubules by virtue of the VLA-4 and LFA-1 on MSC-exos surface. MSC-exos alleviated murine ischemic AKI and decreased the renal tubules injury in a dose-dependent manner. Furthermore, MSC-exos significantly attenuated the cell cycle arrest and apoptosis of TECs both in vivo and in vitro. Mechanistically, miR-125b-5p, which was highly enriched in MSC-exos, repressed the protein expression of p53 in TECs, leading to not only the up-regulation of CDK1 and Cyclin B1 to rescue G2/M arrest, but also the modulation of Bcl-2 and Bax to inhibit TEC apoptosis. Finally, inhibiting miR-125b-5p could mitigate the protective effects of MSC-exos in I/R mice. Conclusion: MSC-exos exhibit preferential tropism to injured kidney and localize to proximal tubules in ischemic AKI. We demonstrate that MSC-exos ameliorate ischemic AKI and promote tubular repair by targeting the cell cycle arrest and apoptosis of TECs through miR-125b-5p/p53 pathway. This study provides a novel insight into the role of MSC-exos in renal tubule repair and highlights the potential of MSC-exos as a promising therapeutic strategy for AKI.

引用

页码：5248 / 5266

页数：19

共 54 条

[1]

In a Phase 1a escalating clinical trial, autologous mesenchymal stem cell infusion for renovascular disease increases blood flow and the glomerular filtration rate while reducing inflammatory biomarkers and blood pressure [J].