Tögel Florian, Weiss Kathleen, Yang Ying, Hu Zhuma, Zhang Ping, Westenfelder Christof
Division of Nephrology, Department of Medicine, University of Utah,Salt Lake City, Utah 84148, USA.
Am J Physiol Renal Physiol. 2007 May;292(5):F1626-35. doi: 10.1152/ajprenal.00339.2006. Epub 2007 Jan 9.
Acute kidney injury (AKI) is a major clinical problem in which a critical vascular, pathophysiological component is recognized. We demonstrated previously that mesenchymal stem cells (MSC), unlike fibroblasts, are significantly renoprotective after ischemia-reperfusion injury and concluded that this renoprotection is mediated primarily by paracrine mechanisms. In this study, we investigated whether MSC possess vasculoprotective activity that may contribute, at least in part, to an improved outcome after ischemia-reperfusion AKI. MSC-conditioned medium contains VEGF, HGF, and IGF-1 and augments aortic endothelial cell (EC) growth and survival, a response not observed with fibroblast-conditioned medium. MSC and EC share vasculotropic gene expression profiles, as both form capillary tubes in vitro on Matrigel alone or in cooperation without fusion. MSC undergo differentiation into an endothelial-like cell phenotype in culture and develop into vascular structures in vivo. Infused MSC were readily detected in the kidney early after reflow but were only rarely engrafted at 1 wk post-AKI. MSC attached in the renal microvascular circulation significantly decreased apoptosis of adjacent cells. Infusion of MSC immediately after reflow in severe ischemia-reperfusion AKI did not improve renal blood flow, renovascular resistance, or outer cortical blood flow. These data demonstrate that the unique vasculotropic, paracrine actions elicited by MSC play a significant renoprotective role after AKI, further demonstrating that cell therapy has promise as a novel intervention in AKI.
急性肾损伤（AKI）是一个重要的临床问题，其中一个关键的血管病理生理成分已得到确认。我们之前证明，与成纤维细胞不同，间充质干细胞（MSC）在缺血再灌注损伤后具有显著的肾脏保护作用，并得出结论，这种肾脏保护作用主要由旁分泌机制介导。在本研究中，我们调查了MSC是否具有血管保护活性，这可能至少部分有助于改善缺血再灌注性AKI后的预后。MSC条件培养基含有血管内皮生长因子（VEGF）、肝细胞生长因子（HGF）和胰岛素样生长因子-1（IGF-1），可促进主动脉内皮细胞（EC）生长和存活，而成纤维细胞条件培养基则未观察到这种反应。MSC和EC具有共同的血管趋化基因表达谱，因为它们在体外单独或协同作用于基质胶上时均能形成毛细血管管腔，且不发生融合。MSC在培养中可分化为内皮样细胞表型，并在体内发育为血管结构。再灌注后早期可在肾脏中轻易检测到注入的MSC，但在AKI后1周仅很少有细胞植入。附着在肾微血管循环中的MSC显著减少了相邻细胞的凋亡。在严重缺血再灌注性AKI再灌注后立即注入MSC并不能改善肾血流量、肾血管阻力或外皮质血流量。这些数据表明，MSC引发的独特血管趋化、旁分泌作用在AKI后发挥了重要的肾脏保护作用，进一步证明细胞治疗有望成为AKI的一种新型干预措施。
