Theranostics 2021; 11(11):5248-5266. doi:10.7150/thno.54550 This issue Cite

Research Paper

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

Jing-Yuan Cao1*, Bin Wang1*, Tao-Tao Tang1*, Yi Wen1, Zuo-Lin Li1, Song-Tao Feng1, Min Wu1, Dan Liu1, Di Yin1, Kun-Ling Ma1, Ri-Ning Tang1, Qiu-Li Wu1, Hui-Yao Lan2, Lin-Li Lv1✉, Bi-Cheng Liu1✉

1. Institute of Nephrology, Zhong Da Hospital, Southeast University School of Medicine, Nanjing 210009, China.
2. Department of Medicine and Therapeutics, Li Ka Shing Institute of Health Sciences, Liu Che Woo Institute of Innovative Medicine, Chinese University of Hong Kong, Hong Kong SAR 999077, China.
*These authors contributed equally to this work.

Citation:
Cao JY, Wang B, Tang TT, Wen Y, Li ZL, Feng ST, Wu M, Liu D, Yin D, Ma KL, Tang RN, Wu QL, Lan HY, Lv LL, Liu BC. Exosomal miR-125b-5p deriving from mesenchymal stem cells promotes tubular repair by suppression of p53 in ischemic acute kidney injury. Theranostics 2021; 11(11):5248-5266. doi:10.7150/thno.54550. https://www.thno.org/v11p5248.htm
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Abstract

Graphic abstract

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.

Keywords: mesenchymal stem cell, exosomes, miR-125b-5p, tubular repair, acute kidney injury


Citation styles

APA
Cao, J.Y., Wang, B., Tang, T.T., Wen, Y., Li, Z.L., Feng, S.T., Wu, M., Liu, D., Yin, D., Ma, K.L., Tang, R.N., Wu, Q.L., Lan, H.Y., Lv, L.L., Liu, B.C. (2021). Exosomal miR-125b-5p deriving from mesenchymal stem cells promotes tubular repair by suppression of p53 in ischemic acute kidney injury. Theranostics, 11(11), 5248-5266. https://doi.org/10.7150/thno.54550.

ACS
Cao, J.Y.; Wang, B.; Tang, T.T.; Wen, Y.; Li, Z.L.; Feng, S.T.; Wu, M.; Liu, D.; Yin, D.; Ma, K.L.; Tang, R.N.; Wu, Q.L.; Lan, H.Y.; Lv, L.L.; Liu, B.C. Exosomal miR-125b-5p deriving from mesenchymal stem cells promotes tubular repair by suppression of p53 in ischemic acute kidney injury. Theranostics 2021, 11 (11), 5248-5266. DOI: 10.7150/thno.54550.

NLM
Cao JY, Wang B, Tang TT, Wen Y, Li ZL, Feng ST, Wu M, Liu D, Yin D, Ma KL, Tang RN, Wu QL, Lan HY, Lv LL, Liu BC. Exosomal miR-125b-5p deriving from mesenchymal stem cells promotes tubular repair by suppression of p53 in ischemic acute kidney injury. Theranostics 2021; 11(11):5248-5266. doi:10.7150/thno.54550. https://www.thno.org/v11p5248.htm

CSE
Cao JY, Wang B, Tang TT, Wen Y, Li ZL, Feng ST, Wu M, Liu D, Yin D, Ma KL, Tang RN, Wu QL, Lan HY, Lv LL, Liu BC. 2021. Exosomal miR-125b-5p deriving from mesenchymal stem cells promotes tubular repair by suppression of p53 in ischemic acute kidney injury. Theranostics. 11(11):5248-5266.

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