Abstract
BackgroundMesenchymal stromal cells (MSCs) and renal stem/progenitors improve the recovery of acute kidney injury (AKI) mainly through the release of paracrine mediators including the extracellular vesicles (EVs). Several studies have reported the existence of a resident population of MSCs within the glomeruli (Gl-MSCs). However, their contribution towards kidney repair still remains to be elucidated. The aim of the present study was to evaluate whether Gl-MSCs and Gl-MSC-EVs promote the recovery of AKI induced by ischemia-reperfusion injury (IRI) in SCID mice. Moreover, the effects of Gl-MSCs and Gl-MSC-EVs were compared with those of CD133+ progenitor cells isolated from human tubules of the renal cortical tissue (T-CD133+ cells) and their EVs (T-CD133+-EVs).MethodsIRI was performed in mice by clamping the left renal pedicle for 35 minutes together with a right nephrectomy. Immediately after reperfusion, the animals were divided in different groups to be treated with: Gl-MSCs, T-CD133+ cells, Gl-MSC-EVs, T-CD133+-EVs or vehicle. To assess the role of vesicular RNA, EVs were either isolated by floating to avoid contamination of non-vesicles-associated RNA or treated with a high dose of RNase. Mice were sacrificed 48 hours after surgery.ResultsGl-MSCs, and Gl-MSC-EVs both ameliorate kidney function and reduce the ischemic damage post IRI by activating tubular epithelial cell proliferation. Furthermore, T-CD133+ cells, but not their EVs, also significantly contributed to the renal recovery after IRI compared to the controls. Floating EVs were effective while RNase-inactivated EVs were ineffective. Analysis of the EV miRnome revealed that Gl-MSC-EVs selectively expressed a group of miRNAs, compared to EVs derived from fibroblasts, which were biologically ineffective in IRI.ConclusionsIn this study, we demonstrate that Gl-MSCs may contribute in the recovery of mice with AKI induced by IRI primarily through the release of EVs.
Highlights
Mesenchymal stromal cells (MSCs) and renal stem/progenitors improve the recovery of acute kidney injury (AKI) mainly through the release of paracrine mediators including the extracellular vesicles (EVs)
Resident population of MSCs within glomeruli (Gl-MSCs) cells are more effective in promoting the recovery of AKI compared to T-CD133+ cells Forty-eight hours after the induction of ischemia-reperfusion injury (IRI), serum creatinine and blood urea nitrogen (BUN) markedly increased in IRI mice compared to healthy and sham-operated mice (Fig. 1)
Injecting mice with Gl-MSCs significantly reduced both functional and histological alterations observed in IRI mice, evaluated 48 hours after surgery (Figs. 1 and 2)
Summary
Mesenchymal stromal cells (MSCs) and renal stem/progenitors improve the recovery of acute kidney injury (AKI) mainly through the release of paracrine mediators including the extracellular vesicles (EVs). Over the last decade, numerous studies performed in animal models of AKI and CKD have reported the beneficial effects of mesenchymal stromal cells (MSCs) in the recovery of renal function after IRI, and in reducing the progression of the chronic damage that followed [17,18,19,20,21,22,23]. It is well known that MSCs release soluble factors which promote the recovery of damaged renal cells [28,29,30,31] Among these factors, extracellular vesicles (EVs) have been implicated to play a role in the paracrine actions of MSCs [32]. Sallustio et al recently reported that the protein decorin carried by EVs from adult renal stem/progenitor cells improved the survival of tubular epithelial cells in an in vitro toxic AKI model [42]
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