Exosomes from human‐bone‐marrow‐derived mesenchymal stem cells protect against renal ischemia/reperfusion injury via transferring miR‐199a‐3p

Abstract

Renal ischemia/reperfusion (I/R) injury is the main reason for acute kidney injury (AKI) and is closely related to high morbidity and mortality. In this study, we found that exosomes from human-bone-marrow-derived mesenchymal stem cells (hBMSC-Exos) play a protective role in hypoxia/reoxygenation (H/R) injury.hBMSC-Exos were enriched in miR-199a-3p, and hBMSC-Exo treatment increased the expression level of miR-199a-3p in renal cells. We further explored the function of miR-199a-3p on H/R injury. miR-199a-3p was knocked down in hBMSCs with a miR-199a-3p inhibitor. HK-2 cells cocultured with miR-199a-3p-knockdown hBMSCs were more susceptible to H/R injury and showed more apoptosis than those cocultured with hBMSCs or miR-199a-3poverexpressing hBMSCs. Meanwhile, we found that HK-2 cells exposed to H/R treatment incubated with hBMSC-Exos decreased semaphorin 3A (Sema3A) and activated the protein kinase B (AKT) and extracellular-signal-regulated kinase (ERK) pathways. However, HK-2 cells cocultured with miR-199a-3p-knockdown hBMSCs restored Sema3A expression and blocked the activation of the AKT and ERK pathways. Moreover, knocking down Sema3A could reactivate the AKT and ERK pathways suppressed by a miR-199a-3p inhibitor. In vivo, we injected hBMSC-Exos into mice suffering from I/R injury; this treatment induced functional recovery and histologic protection and reduced cleaved caspase-3 and Sema3A expression levels, as shown by immunohistochemistry. On the whole, this study demonstrated an antiapoptotic effect of hBMSC-Exos, which protected against I/R injury, via delivering miR-199a-3p to renal cells, downregulating Sema3A expression and thereby activating the AKT and ERK pathways. These findings reveal a novel mechanism of AKI treated with hBMSC-Exos and provide a therapeutic method for kidney diseases. K E Y W O R D S apoptosis, exosomes, human-bone-marrow-derived mesenchymal stem cells, ischemia/reperfusion injury, microRNA SUPPORTING INFORMATION Additional supporting information may be found online in the Supporting Information section. How to cite this article: Zhu G, Pei L, Lin F, et al. Exosomes from human-bone-marrow-derived mesenchymal stem cells protect against renal ischemia/reperfusion injury via transferring miR-199a-3p.

Extracellular vesicles produced by bone marrow mesenchymal stem cells attenuate renal fibrosis, in part by inhibiting the RhoA/ROCK pathway, in a UUO rat model

“…Liu and Zheng [34] found that BMSC transplantation attenuates inflammation, oxidative stress, and fibrosis in skeletal muscle after muscle contusion. In addition, BMSC infusion has been reported to improve recovery from the acute kidney injury (AKI) induced by ischemia/reperfusion [10]. However, BMSCs can also be tumorigenic and are often inappropriately retained by target tissues, limiting their clinical usefulness [9].…”

“…EVs, which are typically approximately 40-200 nm in size [10], can be categorized as exosomes, microvesicles and apoptotic bodies. EVs are membranous bodies that are released by almost all cells [8].…”

“…For a long time, EVs were considered to be debris without any biological function. Recently, however, EVs have attracted great attention in the field of organ regeneration because of the information they package that enables cell-cell communication via fusion with the recipient cell membrane and transfer of biomolecules, such as nucleic acids and proteins [10]. Intra-renal MSC-EVs delivery attenuates tissue inflammation and microvascular loss, which in turn improves stenotickidney hemodynamics.…”

“…Recently it has become increasingly clear that BMSC-derived extracellular vesicles (BMSC-EVs) have important biological functions and molecular mechanisms [9], and may serve as an alternative to therapies based on BMSC transplantation [8]. EVs, which originate from BMSC endosomal compartments, can modulate inflammation [10][11][12]. One study showed that MSC-EVs improve renal function in several animal models of CKD.…”

Roles for Exosome in Various Kidney Diseases and Disorders

“…(Dominguez et al, 2018) Therapeutics MSCs (human) Exosomes derived from bone marrow MSCs were rich with miR-199a-3p and could prevent ischemia/reperfusion-induced AKI by increasing expression of miR-199a-3p in renal cells. (Zhu et al, 2019a) Sepsisinduced AKI Biomarker Urine (human) Increased urinary exosomal NGAL and activating transcription factor 3 in sepsis-induced AKI patients. (Panich et al, 2017) Biomarker…”