Bone Marrow Mesenchymal Stem Cells Ameliorate Cisplatin-Induced Renal Fibrosis via miR-146a-5p/Tfdp2 Axis in Renal Tubular Epithelial Cells

Abstract

Mesenchymal stem cells (MSCs) have regenerative properties in acute kidney injury (AKI). However, the potential function of MSCs in chronic kidney disease remains elusive. Renal fibrosis is the common endpoint of chronic progressive kidney diseases and causes a considerable health burden worldwide. In this study, the protective effects of bone marrow mesenchymal stem cells (BM-MSCs) were assessed in repeated administration of low-dose cisplatin-induced renal fibrosis mouse model in vivo as well as a TGF-β1-induced fibrotic model in vitro. Differentially expressed miRNAs in mouse renal tubular epithelial cells (mRTECs) regulated by BM-MSCs were screened by high-throughput sequencing. We found microRNA (miR)-146a-5p was the most significant up-regulated miRNA in mRTECs. In addition, the gene Tfdp2 was identified as one target gene of miR-146a-5p by bioinformatics analysis. The expression of Tfdp2 in the treatment of BM-MSCs on cisplatin-induced renal injury was evaluated by immunohistochemistry analysis. Our results indicate that BM-MSC attenuates cisplatin-induced renal fibrosis by regulating the miR-146a-5p/Tfdp2 axis in mRTECs.

Amelioration of ligamentum flavum hypertrophy using umbilical cord mesenchymal stromal cell-derived extracellular vesicles

“…Our data also showed that TGF-β1 could effectively promote the expression of Col-I, α-SMA, and Col-III and result in LF cell fibrosis in a dose-dependent manner. According to previous literatures [ 11 , [43] , [44] , [45] ], 10 miRNAs relative to fibrosis were selected as candidates; the RT-qPCR validation of these candidates partially matched the results reported in a previous study [ 46 ]. Since the amelioration of LFH after the EV injection was found, we hypothesised that the miRNAs enriched in the EVs would take responsibility for this amelioration.…”

“…MiR-146a-5p and miR-221-3p have been found to be involved in cell differentiation, proliferation and apoptosis, and they can modulate the inflammatory response and participate in several pathophysiological processes [ [47] , [48] , [49] , [50] , [51] ]. MiR-146a-5p has been demonstrated to reduce hepatic fibrosis [ 52 ], inhibit the expression of fibrosis-related markers in irradiated and TGF-β1-stimulated LX2 cells (human hepatic stellate cell line), reduce skeletal muscle fibrosis after injury, and attenuate cisplatin-induced renal fibrosis [ 44 , 45 , 53 ]. Therefore, miR-221-3p and miR-146a-5p as majorly investigated molecules might be implicated in the progression of LFH, suggesting that upregulation of the expressions of both miRNAs could be a promising strategy for the treatment of LFH.…”

Hypoxic condition induced H3K27me3 modification of the LncRNA Tmem235 promoter thus supporting apoptosis of BMSCs

“…BMSCs have shown good application prospects for treating clinical diseases [34][35][36]. However, the transplanted BMSCs have high rates of apoptosis in the hypoxic environment of the lesion area, which greatly limits the transplantation efficacy of BMSCs [7].…”

Immunomodulatory Effects of Mesenchymal Stem Cells on Drug-Induced Acute Kidney Injury

“…Another mechanism of drug-induced AKI is oxidative stress. Drug nephrotoxicity directly acts on the proximal renal tubules and causes cell damage, such as mitochondrial dysfunction, lysosomal hydrolase inhibition, phospholipid damage, and increased intracellular calcium concentrations, thereby leading to the formation of reactive oxygen species (ROS) (13). The pathogenic mechanisms of ROS have three main aspects: first, nephrotoxic drugs react with cellular antioxidants (such as glutathione) when they are in a highly reactive form (14,15), thus, depleting or inactivating them, leading to the accumulation of endogenous ROS in cells.…”