Instituto de Ciencias, Facultad de Medicina Clínica Alemana Universidad del Desarrollo, Santiago, Chile.
Stem Cells. 2012 Aug;30(8):1664-74. doi: 10.1002/stem.1132.
Type 1 diabetes mellitus (T1DM) is a chronic metabolic disease that results from cell-mediated autoimmune destruction of insulin-producing cells. In T1DM animal models, it has been shown that the systemic administration of multipotent mesenchymal stromal cells, also referred as to mesenchymal stem cells (MSCs), results in the regeneration of pancreatic islets. Mechanisms underlying this effect are still poorly understood. Our aims were to assess whether donor MSCs (a) differentiate into pancreatic β-cells and (b) modify systemic and pancreatic pathophysiologic markers of T1DM. After the intravenous administration of 5 × 10(5) syngeneic MSCs, we observed that mice with T1DM reverted their hyperglycemia and presented no donor-derived insulin-producing cells. In contrast, 7 and 65 days post-transplantation, MSCs were engrafted into secondary lymphoid organs. This correlated with a systemic and local reduction in the abundance of autoaggressive T cells together with an increase in regulatory T cells. Additionally, in the pancreas of mice with T1DM treated with MSCs, we observed a cytokine profile shift from proinflammatory to antinflammatory. MSC transplantation did not reduce pancreatic cell apoptosis but recovered local expression and increased the circulating levels of epidermal growth factor, a pancreatic trophic factor. Therefore, the antidiabetic effect of MSCs intravenously administered is unrelated to their transdifferentiation potential but to their capability to restore the balance between Th1 and Th2 immunological responses along with the modification of the pancreatic microenvironment. Our data should be taken into account when designing clinical trials aimed to evaluate MSC transplantation in patients with T1DM since the presence of endogenous precursors seems to be critical in order to restore glycemic control.
1 型糖尿病（T1DM）是一种慢性代谢性疾病，由胰岛素产生细胞的细胞介导的自身免疫破坏引起。在 T1DM 动物模型中，已经表明全身性给予多能间充质基质细胞，也称为间充质干细胞（MSCs），可导致胰岛的再生。这种作用的机制仍知之甚少。我们的目的是评估供体 MSC（a）是否分化为胰岛 β 细胞，以及（b）是否改变 T1DM 的全身和胰腺病理生理标志物。在静脉内给予 5×10(5)个同种异体 MSC 后，我们观察到患有 T1DM 的小鼠逆转了高血糖，并且没有供体衍生的胰岛素产生细胞。相比之下，在移植后 7 天和 65 天，MSC 被植入次级淋巴器官。这与系统性和局部自身反应性 T 细胞丰度降低以及调节性 T 细胞增加相关。此外，在接受 MSC 治疗的 T1DM 小鼠的胰腺中，我们观察到细胞因子谱从促炎转变为抗炎。MSC 移植并未减少胰腺细胞凋亡，但恢复了局部表达并增加了循环表皮生长因子水平，表皮生长因子是一种胰腺营养因子。因此，静脉内给予 MSC 的抗糖尿病作用与其转分化潜力无关，而是与其恢复 Th1 和 Th2 免疫反应之间的平衡以及修饰胰腺微环境的能力有关。在设计旨在评估 T1DM 患者 MSC 移植的临床试验时，应该考虑到我们的数据，因为内源性前体的存在对于恢复血糖控制似乎至关重要。
