Ranghino Andrea, Bruno Stefania, Bussolati Benedetta, Moggio Aldo, Dimuccio Veronica, Tapparo Marta, Biancone Luigi, Gontero Paolo, Frea Bruno, Camussi Giovanni
Department of Medical Sciences and Molecular Biotechnology Center, University of Torino, Corso Dogliotti 14, Torino, 10126, Italy.
Department of Molecular Biotechnology and Health Sciences and Molecular Biotechnology Center, University of Torino, Torino, Italy.
Stem Cell Res Ther. 2017 Feb 7;8(1):24. doi: 10.1186/s13287-017-0478-5.
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). 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).
IRI 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.
Gl-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.
In 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.
间充质基质细胞（MSCs）和肾干/祖细胞主要通过释放包括细胞外囊泡（EVs）在内的旁分泌介质来促进急性肾损伤（AKI）的恢复。多项研究报道肾小球内存在常驻的MSCs群体（Gl-MSCs）。然而，它们对肾脏修复的贡献仍有待阐明。本研究的目的是评估Gl-MSCs和Gl-MSC-EVs是否能促进重症联合免疫缺陷（SCID）小鼠缺血再灌注损伤（IRI）诱导的AKI的恢复。此外，将Gl-MSCs和Gl-MSC-EVs的作用与从肾皮质组织人肾小管分离的CD133祖细胞（T-CD133细胞）及其EVs（T-CD133-EVs）的作用进行了比较。
通过夹闭左肾蒂35分钟并同时切除右肾进行小鼠IRI。再灌注后立即将动物分为不同组，分别用Gl-MSCs、T-CD133细胞、Gl-MSC-EVs、T-CD133-EVs或赋形剂处理。为评估囊泡RNA的作用，通过漂浮分离EVs以避免非囊泡相关RNA的污染，或用高剂量核糖核酸酶处理。术后48小时处死小鼠。
Gl-MSCs和Gl-MSC-EVs均通过激活肾小管上皮细胞增殖改善肾功能并减少IRI后的缺血损伤。此外，与对照组相比，T-CD133细胞而非其EVs也对IRI后的肾脏恢复有显著贡献。漂浮的EVs有效，而核糖核酸酶灭活的EVs无效。对EV微小RNA组的分析显示，与成纤维细胞来源的在IRI中无生物学活性的EVs相比，Gl-MSC-EVs选择性表达一组微小RNA。
在本研究中，我们证明Gl-MSCs可能主要通过释放EVs促进IRI诱导AKI小鼠的恢复。
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