PMID- 33859745
OWN - NLM
STAT- MEDLINE
DCOM- 20210728
LR  - 20220218
IS  - 1838-7640 (Electronic)
IS  - 1838-7640 (Linking)
VI  - 11
IP  - 11
DP  - 2021
TI  - Exosomal miR-125b-5p deriving from mesenchymal stem cells promotes tubular repair 
      by suppression of p53 in ischemic acute kidney injury.
PG  - 5248-5266
LID - 10.7150/thno.54550 [doi]
AB  - 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.
CI  - (c) The author(s).
FAU - Cao, Jing-Yuan
AU  - Cao JY
AD  - Institute of Nephrology, Zhong Da Hospital, Southeast University School of 
      Medicine, Nanjing 210009, China.
FAU - Wang, Bin
AU  - Wang B
AD  - Institute of Nephrology, Zhong Da Hospital, Southeast University School of 
      Medicine, Nanjing 210009, China.
FAU - Tang, Tao-Tao
AU  - Tang TT
AD  - Institute of Nephrology, Zhong Da Hospital, Southeast University School of 
      Medicine, Nanjing 210009, China.
FAU - Wen, Yi
AU  - Wen Y
AD  - Institute of Nephrology, Zhong Da Hospital, Southeast University School of 
      Medicine, Nanjing 210009, China.
FAU - Li, Zuo-Lin
AU  - Li ZL
AD  - Institute of Nephrology, Zhong Da Hospital, Southeast University School of 
      Medicine, Nanjing 210009, China.
FAU - Feng, Song-Tao
AU  - Feng ST
AD  - Institute of Nephrology, Zhong Da Hospital, Southeast University School of 
      Medicine, Nanjing 210009, China.
FAU - Wu, Min
AU  - Wu M
AD  - Institute of Nephrology, Zhong Da Hospital, Southeast University School of 
      Medicine, Nanjing 210009, China.
FAU - Liu, Dan
AU  - Liu D
AD  - Institute of Nephrology, Zhong Da Hospital, Southeast University School of 
      Medicine, Nanjing 210009, China.
FAU - Yin, Di
AU  - Yin D
AD  - Institute of Nephrology, Zhong Da Hospital, Southeast University School of 
      Medicine, Nanjing 210009, China.
FAU - Ma, Kun-Ling
AU  - Ma KL
AD  - Institute of Nephrology, Zhong Da Hospital, Southeast University School of 
      Medicine, Nanjing 210009, China.
FAU - Tang, Ri-Ning
AU  - Tang RN
AD  - Institute of Nephrology, Zhong Da Hospital, Southeast University School of 
      Medicine, Nanjing 210009, China.
FAU - Wu, Qiu-Li
AU  - Wu QL
AD  - Institute of Nephrology, Zhong Da Hospital, Southeast University School of 
      Medicine, Nanjing 210009, China.
FAU - Lan, Hui-Yao
AU  - Lan HY
AD  - 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.
FAU - Lv, Lin-Li
AU  - Lv LL
AD  - Institute of Nephrology, Zhong Da Hospital, Southeast University School of 
      Medicine, Nanjing 210009, China.
FAU - Liu, Bi-Cheng
AU  - Liu BC
AD  - Institute of Nephrology, Zhong Da Hospital, Southeast University School of 
      Medicine, Nanjing 210009, China.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20210311
PL  - Australia
TA  - Theranostics
JT  - Theranostics
JID - 101552395
RN  - 0 (Cyclin B1)
RN  - 0 (MicroRNAs)
RN  - 0 (Mirn125 microRNA, mouse)
RN  - 0 (Proto-Oncogene Proteins c-bcl-2)
RN  - 0 (TP53 protein, human)
RN  - 0 (Tumor Suppressor Protein p53)
RN  - 0 (bcl-2-Associated X Protein)
RN  - EC 2.7.11.22 (CDC2 Protein Kinase)
SB  - IM
MH  - Acute Kidney Injury/*genetics/physiopathology
MH  - Animals
MH  - Apoptosis/genetics
MH  - CDC2 Protein Kinase/genetics
MH  - Cell Cycle Checkpoints/genetics
MH  - Cell Division/genetics
MH  - Cell Line
MH  - Cell Proliferation/genetics
MH  - Cyclin B1/genetics
MH  - Epithelial Cells/physiology
MH  - Exosomes/*genetics
MH  - G2 Phase/genetics
MH  - Humans
MH  - Ischemia/genetics/physiopathology
MH  - Kidney Tubules, Proximal/*physiology
MH  - Male
MH  - Mesenchymal Stem Cells/*physiology
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - MicroRNAs/*genetics
MH  - Proto-Oncogene Proteins c-bcl-2/genetics
MH  - Reperfusion Injury/*genetics/physiopathology
MH  - Tissue Distribution/genetics
MH  - Tumor Suppressor Protein p53/*genetics
MH  - bcl-2-Associated X Protein/genetics
PMC - PMC8039965
OTO - NOTNLM
OT  - acute kidney injury
OT  - exosomes
OT  - mesenchymal stem cell
OT  - miR-125b-5p
OT  - tubular repair
COIS- Competing Interests: The authors have declared that no competing interest exists.
EDAT- 2021/04/17 06:00
MHDA- 2021/07/29 06:00
PMCR- 2021/01/01
CRDT- 2021/04/16 06:36
PHST- 2020/10/15 00:00 [received]
PHST- 2021/02/18 00:00 [accepted]
PHST- 2021/04/16 06:36 [entrez]
PHST- 2021/04/17 06:00 [pubmed]
PHST- 2021/07/29 06:00 [medline]
PHST- 2021/01/01 00:00 [pmc-release]
AID - thnov11p5248 [pii]
AID - 10.7150/thno.54550 [doi]
PST - epublish
SO  - Theranostics. 2021 Mar 11;11(11):5248-5266. doi: 10.7150/thno.54550. eCollection 
      2021.