BMSCs protect against renal ischemia‐reperfusion injury by secreting exosomes loaded with miR‐199a‐5p that target BIP to inhibit endoplasmic reticulum stress at the very early reperfusion stages

Abstract

Bone marrow–derived mesenchymal stem cells (BMSCs) have been recently reported to play a variety of vital roles in organ and tissue damage repair, mainly via potent paracrine activity, including secreting extracellular vesicles, such as exosomes, that serve as mediators facilitating intercellular communication and reprogramming recipient cells by delivering their contents to target cells. However, the underlying mechanisms are diverse and complex, and the influencing characteristics have rarely been studied. Accordingly, we designed this study to explore the time dependence of the effects of exosomes derived from BMSCs (BMexos) on renal ischemia‐reperfusion (I/R) injury and the underlying mechanisms associated with the reperfusion time. Impressively, our study is the first to find that BMexos protected against renal I/R injury in vitro and in vivo at the very early reperfusion stages, especially 4–8 h after reperfusion in vitro and 8–16 h after reperfusion in vivo. Interestingly, we simultaneously found that endoplasmic reticulum (ER) stress was significantly suppressed following the administration of BMexos in vitro and in vivo with a similar time dependence. Additionally, we discovered that miR‐199a‐5p, which was abundant in the BMSCs, was transferred into renal tubular epithelial cells (NRK‐52E) in a time‐dependent manner and significantly inhibited I/R‐induced ER stress by targeting binding immunoglobulin protein (BIP). Cocultivation with miR‐199a‐5p‐overexpressing BMSCs amplified the suppression of ER stress and further protected against I/R injury. However, coculture with miR‐199a‐5p‐knockdown BMSCs obviously increased ER stress and reversed the BMexos‐induced protection, and silencing BIP by small interfering RNA–1098 in NRK‐52E inhibited these effects. This study provides evidence that administering BMexos at the very early reperfusion stages significantly protects against renal I/R injury, and ER stress is closely linked to this protection. These results suggest a novel therapeutic strategy during the very early reperfusion stages of renal I/R injury.—Wang, C., Zhu, G., He, W., Yin, H., Lin, F., Gou, X., Li, X. BMSCs protect against renal ischemia‐reperfusion injury by secreting exosomes loaded with miR‐199a‐5p that target BIP to inhibit endoplasmic reticulum stress at the very early reperfusion stages. FASEB J. 33, 5440–5456 (2019). http://www.fasebj.org

Exosome-shuttled miR-216a-5p from hypoxic preconditioned mesenchymal stem cells repair traumatic spinal cord injury by shifting microglial M1/M2 polarization

“…A recent study demonstrated, with a myocardial infarction model, that the beneficial effects of MSC transplantation are mediated by exosomes, which shuttled miR-125b-5p by targeting Bnip3 [82]. It has also been found that BMSCs protect against I/R by secreting exosomes loaded with miR-199a-5p by targeting BIP [83]. Another study showed that BMSC-derived exosomes could modulate age-related insulin resistance by the transfer of functional exosomal miR-29b-3p and thereby inhibit the expression of the target gene SIRT1 [84].…”

Exosomal miR‐1246 derived from human umbilical cord blood mesenchymal stem cells attenuates hepatic ischemia reperfusion injury by modulating T helper 17/regulatory T balance

“…Li et al confirmed that bone marrow MSCs protected against lung IRI by secreting exosomes loaded with miR‐21‐5p . Wang et al manifested that MSCs ameliorated renal IRI in an exosomal miR‐199a‐5p‐dependent manner . Although a growing body of evidence demonstrated the protection of MSCs against hepatic IRI by secreting exosomes, the underlying mechanisms have rarely been reported.…”

Enhanced therapeutic effects of MSC-derived extracellular vesicles with an injectable collagen matrix for experimental acute kidney injury treatment

“…Using the renal I/R model, we discovered that increased ER stress leads to more apoptosis and damage; inhibition of ER stress enhances EV-induced protection against renal I/R injury. A series of studies have shown that the response to increasing unfolded and misfolded proteins causes GRP78 to dissociate from the ER stress sensor, while free GRP78 levels determine the activation of UPR, which may trigger cell death under ER stress [49][50][51][52]. Therefore, the regulation of GRP78 has a close impact on the ER stress process.…”