1. Small extracellular vesicles-shuttled miR-23a-3p from mesenchymal stem cells alleviate renal fibrosis and inflammation by inhibiting KLF3/STAT3 axis in diabetic kidney disease.
- Author
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Li Q, Liu J, Su R, Zhen J, Liu X, and Liu G
- Subjects
- Animals, Humans, Mice, Male, Signal Transduction, Cell Line, Mice, Inbred C57BL, Kidney pathology, Kidney metabolism, Inflammation, MicroRNAs genetics, MicroRNAs metabolism, Diabetic Nephropathies therapy, Diabetic Nephropathies genetics, Diabetic Nephropathies metabolism, Mesenchymal Stem Cells metabolism, Extracellular Vesicles metabolism, Extracellular Vesicles transplantation, STAT3 Transcription Factor metabolism, STAT3 Transcription Factor genetics, Kruppel-Like Transcription Factors metabolism, Kruppel-Like Transcription Factors genetics, Fibrosis
- Abstract
Human umbilical cord mesenchymal stem cells-derived small extracellular vesicles (MSC-sEV) provide a pragmatic solution as a cell-free therapy for patients with diabetic kidney disease (DKD). However, the underlying protective mechanisms of MSC-sEV remain largely unknown in DKD. Invivo and in vitro analyses demonstrated that MSC-sEV attenuated renal fibrosis and inflammation of DKD. The underlying mechanism of the MSC-sEV-induced therapeutic effect was explored by high-throughput sequencing, which identified the unique enrichment of a set of miRNAs in MSC-sEV compared with human skin fibroblasts-sEV (HSF-sEV). Vitro experiments demonstrated that the protective potential was primarily attributed to miR-23a-3p, one of the most abundant miRNAs in MSC-sEV. Further, overexpression or knockdown analyses revealed that miR-23a-3p, and its target Krüppel-like factor 3 (KLF3) suppressed the STAT3 signaling pathway in high glucose (HG) induced HK-2 cells were essential for the renal-protective property of MSC-sEV. Moreover, we found that miR-23a-3p was packaged into MSC-sEV by RNA Binding Motif Protein X-Linked (RBMX) and transmitted to HG-induced HK-2 cells. Finally, inhibiting miR-23a-3p could mitigate the protective effects of MSC-sEV in db/db mice. These findings suggest that a systemic administration of sEV derived from MSC, have the capacity to incorporate into kidney where they can exert renal-protective potential against HG-induced injury through delivery of miR-23a-3p., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)
- Published
- 2024
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