Bone mesenchymal stem cells ameliorate ischemia/reperfusion-induced damage in renal epithelial cells via microRNA-223

Abstract

BackgroundRecent studies have indicated that microRNA-223 (miR-223) plays a role in the tissue-protective effect of mesenchymal stem cells (MSCs). NLR family-pyrin domain containing 3 (NLRP3) was reported to affect a renal ischemia/reperfusion (I/R) injury by exerting a direct effect on the renal tubular epithelium. Therefore, we investigated how miR-223 and NLRP3 might function in kidneys exposed to conditions of ischemia and subsequent reperfusion.MethodsHypoxia/reoxygenation (H/R) murine renal tubular epithelial cells (RTECs) were cocultured with either MSCs or hypoxia-pretreated MSCs (htMSCs), after which the RTECs were examined for their viability and evidence of apoptosis. Next, miR-223 expression in the MSCs was downregulated to verify that MSCs protected RTECs via the transport of miR-223. Kidney I/R KM/NIH mouse models were created and used for in vivo studies.ResultsThe results showed that coculture with MSCs significantly increased the viability of RTECs and decreased their rates of apoptosis. The levels of hepatocyte growth factor (HGF), insulin-like growth factor-1 (IGF-1), transforming growth factor beta (TGF-β), and vascular endothelial growth factor (VEGF) in samples of coculture supernatants were higher than those in samples of non-coculture supernatants. A bioinformatics analysis revealed a targeting relationship between miR-223 and NLRP3. A dual luciferase assay showed that miR-223 inhibited NLRP3 expression. The htMSCs displayed a protective function associated with an upregulation of miR-223 as induced by Notch1 and the downregulation of NLRP3. Conversely, inhibition of miR-223 impeded the protective effect of MSCs. In the I/R mouse models, injection of either MSCs or htMSCs ameliorated the damage to kidney tissue, while suppression of miR-223 expression in MSCs reduced their protective effect on mouse kidneys.ConclusionsOur results demonstrate that miR-223 and NLRP3 play important roles in the treatment of renal tissue injuries with transplanted MSCs.

Immunomodulatory and Regenerative Effects of Mesenchymal Stem Cell-Derived Extracellular Vesicles in Renal Diseases

“…The mechanism regulating cell apoptosis is one of the most important aspects of renal protection. Indeed, the anti-apoptotic pathway has been reported in many studies with MSC-EVs treatment in a variety of rodent renal injury models, including AKI induced by I/R [24,31,33,104,106,[116][117][118]120,124,125], cisplatin [48,119,126], gentamicin [105], and glycerol [17], hypoxia-induced renal injury [60], aldosterone-induced renal injury [52], and UUO-induced CKD model [109]. Recent advances have gradually uncovered the specific miRNAs, their targets and signaling pathways involved in the effect of anti-apoptosis (Table 2), including PTEN, AKT, mTOR, dynamin-related protein 1 (DRP1), Sema3A, and ERK signaling pathway.…”

AMSC-derived exosomes alleviate lipopolysaccharide/d-galactosamine-induced acute liver failure by miR-17-mediated reduction of TXNIP/NLRP3 inflammasome activation in macrophages

“…Several studies have shown that MSCs can attenuate collagen-induced arthritis, coxsackievirus B3-induced myocarditis, or ischemia/reperfusion (I/R)-induced renal injury by inhibiting NLRP3 inflammasome activation [ [12] , [13] , [14] ]. However, whether AMSC-Exo-based therapy can ameliorate ALF and modulate NLRP3 inflammasome is unclear.…”

Mesenchymal Stem Cell-Derived Extracellular Vesicles: A Novel Cell-Free Therapy for Sepsis

“…In AKI mice models induced by ischemia-reperfusion injury, Bruno et al (27) found that MSC-EVs induced the expression of anti-apoptotic genes (Bcl-XL, Bcl2, and BIRC8) in renal tubular epithelial cells while simultaneously down-regulating pro-apoptotic genes (Casp1, Casp8, and LTA), thus reducing tubular cell apoptosis and conferring an anti-apoptotic phenotype necessary for tissue repair. Interestingly, the anti-apoptosis effect of MSC-EVs may be mediated in part by the transfer of miRNAs (miR-223 and miR-199a-3p) to tubular cells (54,55). In addition, MSC-EVs can directly shuttle several pro-angiogenesis transcription factors including vascular endothelial growth factor (VEGF) (52), insulin-like growth factor 1 (IGF-1) (56), and basic fibroblast growth factor (bFGF) (57) to the damaged renal tubular epithelial cells and enhance angiogenesis, which is considered as an important step in tissue regeneration.…”