Clinic for Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Stem Cells Dev. 2010 May;19(5):719-29. doi: 10.1089/scd.2009.0494.
We demonstrated previously that administration of mesenchymal stromal cells (MSCs) after renal ischemia/reperfusion injury (IRI) in rats protected renal function and hastened repair through complex paracrine mechanisms. Here we investigated kidney-protective actions of MSCs in a porcine IRI model that may have relevance to human acute kidney injury (AKI). Groups of female pigs with bilateral IRI were infused with autologous or male allogeneic MSCs. No acute or late complications were observed, but unexpectedly, MSC therapy also had no beneficial effects on kidney function and histology. In vitro, we demonstrated substantial functional and phenotypic overlaps between rodent, human, and porcine MSCs, all of which exhibited trilineage differentiation, characteristic antigen profiles, and secretion of renoprotective vascular endothelial growth factor (VEGF)-A and insulin-like growth factor-1 (IGF-1). However, in striking contrast to human MSCs, porcine MSCs failed to inhibit the mixed lymphocyte reaction (MLR) and induced robust production of proinflammatory interleukin-6 (IL-6). In summary, in contrast to rodent models, treatment of porcine IRI with MSCs was not kidney-protective. This, we conclude, is due to the fact that porcine MSCs exert inadequate immune-modulating effects, further demonstrating that successful therapy of IRI with MSCs critically depends on their anti-inflammatory actions. As a consequence, treatment of AKI with MSCs is not informative regarding the investigation of the underlying mechanisms in this large animal model. We expect, however, that the treatment of human IRI of the kidney with immune-modulating MSCs will be as effective as in rodent models.
我们之前已经证明，在大鼠肾缺血/再灌注损伤（IRI）后给予间充质基质细胞（MSCs）可通过复杂的旁分泌机制保护肾功能并加速修复。在这里，我们在可能与人类急性肾损伤（AKI）相关的猪 IRI 模型中研究了 MSCs 的肾脏保护作用。接受双侧 IRI 的雌性猪组接受了自体或雄性同种异体 MSCs 的输注。未观察到急性或迟发性并发症，但出乎意料的是，MSC 治疗对肾功能和组织学也没有有益作用。在体外，我们证明了啮齿动物、人类和猪 MSCs 之间存在大量功能和表型重叠，所有这些细胞均表现出三系分化、特征性抗原谱以及肾保护血管内皮生长因子（VEGF）-A 和胰岛素样生长因子-1（IGF-1）的分泌。然而，与人类 MSCs 形成鲜明对比的是，猪 MSCs 未能抑制混合淋巴细胞反应（MLR），并诱导促炎细胞因子白细胞介素-6（IL-6）的大量产生。总之，与啮齿动物模型相反，用 MSCs 治疗猪 IRI 没有肾脏保护作用。我们的结论是，这是由于猪 MSCs 发挥的免疫调节作用不足所致，进一步证明了 MSCs 成功治疗 IRI 取决于其抗炎作用。因此，用 MSCs 治疗 AKI 并不能为研究该大型动物模型中的潜在机制提供信息。然而，我们预计用免疫调节 MSC 治疗人类肾 IRI 将与啮齿动物模型一样有效。
