Department of Neurology and Laboratory of Neuroscience, Centro Dino Ferrari, Università degli Studi di Milano-IRCCS Istituto Auxologico Italiano, 20149 Milan, Italy.
Brain Res. 2010 Jan 22;1311:12-27. doi: 10.1016/j.brainres.2009.11.041. Epub 2009 Nov 26.
Stimulation of endogenous repair in neurodegenerative diseases, such as Parkinson's disease (PD), appears to be a novel and promising therapeutic application of stem cells (SCs). In fact SCs could propel local microenvironmental signals to sustain active endeavors for damaged neurons substitution, normally failing in non-supportive pathological surroundings. In this study, we demonstrated that two different doses of naïve human adult mesenchymal stem cells (hMSCs), implanted in the striatum of rats lesioned with 6-hydroxydopamine (6-OHDA), positively survived 23 days after transplantation. Their fate was directly influenced by the surrounding host environment while grafted hMSCs, dose dependently, regionally sustained the survival of striatal/nigral dopaminergic terminals and enhanced neurogenesis in the Subventricular Zone (SVZ). The number of proliferative cells (Ki67/Proliferating Cell Nuclear Antigen +) as well as neuroblasts migration significantly augmented in the lesioned striatum of transplanted animals compared to controls. No SVZ astrogenesis was detected in all experimental conditions, irrespectively of graft presence. Activation of endogenous stem cell compartments and rescue of dopaminergic neurons, supported by the persistent release of specific cytokine by MSCs in vivo, appeared in principle able to contrast the neurodegenerative processes induced by the 6-OHDA lesion. Our results suggest that reciprocal influences between grafted cells and endogenous neural precursors could be important for the observed neurorescue effect on several brain regions. Altogether, our data provide remarkable cues regarding the potential of hMSCs in promoting endogenous reparative mechanisms that may prove applicable and beneficial for PD treatment.
刺激神经退行性疾病（如帕金森病）中的内源性修复似乎是干细胞（SCs）的一种新颖且有前途的治疗应用。事实上，SCs 可以推动局部微环境信号，以维持受损神经元替代的积极努力，而在非支持性的病理环境中，这种替代通常会失败。在这项研究中，我们证明了两种不同剂量的幼稚人成体间充质干细胞（hMSCs），在被 6-羟多巴胺（6-OHDA）损伤的大鼠纹状体中植入后，在移植后 23 天内阳性存活。它们的命运直接受到周围宿主环境的影响，而移植的 hMSCs 则依赖于剂量，区域维持纹状体/黑质多巴胺能末梢的存活，并增强侧脑室下区（SVZ）中的神经发生。与对照组相比，在移植动物的损伤纹状体中，增殖细胞（Ki67/增殖细胞核抗原+）的数量以及神经前体细胞的迁移明显增加。在所有实验条件下，无论是否存在移植物，均未检测到 SVZ 星形胶质细胞发生。内源性干细胞区室的激活和多巴胺能神经元的挽救，由 MSC 在体内持续释放特定细胞因子来支持，原则上能够对抗 6-OHDA 损伤引起的神经退行性过程。我们的结果表明，移植物细胞和内源性神经前体细胞之间的相互影响可能对观察到的对多个脑区的神经保护作用很重要。总之，我们的数据为 hMSCs 在促进内源性修复机制方面的潜力提供了重要线索，这些机制可能适用于并有益于 PD 的治疗。
