Mesenchymal Stem Cells Attenuate Renal Fibrosis Through Immune Modulation and Remodeling Properties in a Rat Remnant Kidney Model
Mesenchymal Stem Cells Attenuate Renal Fibrosis Through Immune Modulation and Remodeling Properties in a Rat Remnant Kidney Model
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DOI：
10.1002/stem.214
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发表时间：
2009-12-01
期刊：
影响因子：
5.2
通讯作者：
Saraiva Camara, Niels Olsen
中科院分区：
文献类型：
--
作者：
Semedo, Patricia;Correa-Costa, Matheus;Saraiva Camara, Niels Olsen
间充质干细胞（MSC）在急性肾损伤中具有再生特性，但其在慢性肾脏疾病中的作用仍不清楚。更具体地说，尚不清楚MSC是否阻止纤维化。本研究的目的是利用慢性肾功能衰竭模型研究间充质干细胞在纤维形成中的作用。从雄性Wistar大鼠的胫骨和股骨获得MSC。对雌性Wistar大鼠进行残余模型，并且每隔一周向每只大鼠静脉内施用2个竖条× 10（5）个竖条的MSC，持续8周或仅一次并随后12周。用雄性MSCs处理雌性大鼠，观察SRY基因表达，并在8周时评估CD 73（+）CD 90（+）细胞的免疫定位。血清和尿液分析显示，MSC治疗的动物在8周时功能参数改善，但在12周时没有改善。Masson三色和天狼星红染色显示MSC处理的动物中纤维化水平降低。波形蛋白、I型胶原、转化生长因子β、成纤维细胞特异性蛋白1（FSP-1）、单核细胞趋化蛋白1和Smad 3 mRNA表达以及α平滑肌肌动蛋白和FSP-1蛋白表达减少证实了这些结果。MSC治疗后，肾白细胞介素（IL）-6和肿瘤坏死因子α mRNA的表达水平显着下降，而IL-4和IL-10的表达水平增加。MSC处理的动物中所有血清细胞因子表达水平均降低。总之，这些结果表明，MSC治疗确实可以调节慢性肾损伤初始阶段后的炎症反应。骨髓间充质干细胞的免疫抑制和重塑特性可能与肾脏纤维化的减少有关。干细胞2009;27：3063-3073
Mesenchymal stem cells (MSCs) have regenerative properties in acute kidney injury, but their role in chronic kidney diseases is still unknown. More specifically, it is not known whether MSCs halt fibrosis. The purpose of this work was to investigate the role of MSCs in fibrogenesis using a model of chronic renal failure. MSCs were obtained from the tibias and femurs of male Wistar-EPM rats. Female Wistar rats were subjected to the remnant model, and 2 vertical bar x vertical bar 10(5) MSCs were intravenously administrated to each rat every other week for 8 weeks or only once and followed for 12 weeks. SRY gene expression was observed in female rats treated with male MSCs, and immune localization of CD73(+)CD90(+) cells at 8 weeks was also assessed. Serum and urine analyses showed an amelioration of functional parameters in MSC-treated animals at 8 weeks, but not at 12 weeks. Masson's trichrome and Sirius red staining demonstrated reduced levels of fibrosis in MSC-treated animals. These results were corroborated by reduced vimentin, type I collagen, transforming growth factor beta, fibroblast specific protein 1 (FSP-1), monocyte chemoattractant protein 1, and Smad3 mRNA expression and alpha smooth muscle actin and FSP-1 protein expression. Renal interleukin (IL)-6 and tumor necrosis factor alpha mRNA expression levels were significantly decreased after MSC treatment, whereas IL-4 and IL-10 expression levels were increased. All serum cytokine expression levels were decreased in MSC-treated animals. Taken together, these results suggested that MSC therapy can indeed modulate the inflammatory response that follows the initial phase of a chronic renal injury. The immunosuppressive and remodeling properties of MSCs may be involved in the decreased fibrosis in the kidney. STEM CELLS 2009;27:3063-3073