Department of Urology, Indiana University School of Medicine, Indianapolis, Indianapolis, Indiana 46202, USA.
J Surg Res. 2011 Jun 1;168(1):e51-9. doi: 10.1016/j.jss.2010.06.022. Epub 2010 Jul 8.
Mesenchymal stem cells (MSCs) hold promise for the treatment of renal disease. While MSCs have been shown to accelerate recovery and prevent acute renal failure in multiple disease models, the effect of MSC therapy on chronic obstruction-induced renal fibrosis has not previously been evaluated.
Male Sprague-Dawley rats underwent renal artery injection of vehicle or fluorescent-labeled human bone marrow-derived MSCs immediately prior to sham operation or induction of left ureteral obstruction (UUO). One or 4 wk later, the kidneys were harvested and the renal cortex analyzed for evidence of stem cell infiltration, epithelial-mesenchymal transition (EMT) as evidenced by E-cadherin/α-smooth muscle actin (α-SMA) expression and fibroblast specific protein (FSP+) staining, renal fibrosis (collagen content, Masson's trichrome staining), and cytokine and growth factor activity (ELISA and real time RT-PCR).
Fluorescent-labeled MSCs were detected in the interstitium of the kidney up to 4 wk post-obstruction. Arterially delivered MSCs significantly reduced obstruction-induced α-SMA expression, FSP+ cell accumulation, total collagen content, and tubulointerstitial fibrosis, while simultaneously preserving E-cadherin expression, suggesting that MSCs prevent obstruction-induced EMT and renal fibrosis. Exogenous MSCs reduced obstruction-induced tumor necrosis factor-α (TNF-α) levels, but did not alter transforming growth factor-β1 (TGF-β1), vascular endothelial growth factor (VEGF), interleukin-10 (IL-10), fibroblast growth factor (FGF), or hepatocyte growth factor (HGF) expression.
Human bone marrow-derived MSCs remain viable several weeks after delivery into the kidney and provide protection against obstruction-induced EMT and chronic renal fibrosis. While the mechanism of MSCs-induced renal protection during obstruction remains unclear, our results demonstrate that alterations in TNF-α production may be involved.
间充质干细胞（MSCs）在治疗肾脏疾病方面具有广阔的应用前景。尽管已有研究表明 MSCs 可加速多种疾病模型的恢复并预防急性肾衰竭，但 MSCs 治疗对慢性梗阻性诱导的肾纤维化的影响尚未得到评估。
雄性 Sprague-Dawley 大鼠在假手术或左输尿管梗阻（UUO）诱导前立即进行肾动脉注射载体或荧光标记的人骨髓源性 MSCs。1 或 4 周后，收获肾脏，分析肾皮质以评估干细胞浸润、上皮-间充质转化（EMT）的证据，表现为 E-钙黏蛋白/α-平滑肌肌动蛋白（α-SMA）表达和成纤维细胞特异性蛋白（FSP+）染色、肾纤维化（胶原含量、马松三色染色）以及细胞因子和生长因子活性（ELISA 和实时 RT-PCR）。
在梗阻后 4 周内，荧光标记的 MSCs 可在肾脏间质中检测到。动脉内给予 MSCs 可显著减少梗阻诱导的α-SMA 表达、FSP+细胞积聚、总胶原含量和肾小管间质纤维化，同时保留 E-钙黏蛋白表达，提示 MSCs 可预防梗阻诱导的 EMT 和肾纤维化。外源性 MSCs 降低了梗阻诱导的肿瘤坏死因子-α（TNF-α）水平，但不改变转化生长因子-β1（TGF-β1）、血管内皮生长因子（VEGF）、白细胞介素-10（IL-10）、成纤维细胞生长因子（FGF）或肝细胞生长因子（HGF）的表达。
人骨髓源性 MSCs 在输注到肾脏后数周仍保持活力，并为梗阻诱导的 EMT 和慢性肾纤维化提供保护。虽然 MSCs 在梗阻期间诱导肾保护的机制尚不清楚，但我们的结果表明，TNF-α 产生的改变可能参与其中。
