Department of Neurological, Neuropsychological, Morphological and Movement Sciences, Neurology Section, University of Verona, Verona, Italy.
Tissue Eng Part A. 2012 Jun;18(11-12):1264-72. doi: 10.1089/ten.TEA.2011.0491. Epub 2012 Apr 3.
Mesenchymal stem cells (MSCs) represent a promising therapeutic approach in nerve tissue engineering. To date, the local implantation of MSC in injured nerves has been the only route of administration used. In case of multiple sites of injury, the systemic administration of cells capable of reaching damaged nerves would be advisable. In this regard, we found that an intravenous administration of adipose-derived MSC (ASC) 1 week after sciatic nerve crush injury, a murine model of acute axonal damage, significantly accelerated the functional recovery. Sciatic nerves from ASC-treated mice showed the presence of a restricted number of undifferentiated ASC together with a significant improvement in fiber sprouting and the reduction of inflammatory infiltrates for up to 3 weeks. Besides the immune modulatory effect, our results show that ASC may contribute to peripheral nerve regeneration because of their ability to produce in culture neuroprotective factors such as insulin-like growth factor I, brain-derived neurotrophic factor, or basic fibroblast growth factor. In addition to this production in vitro, we interestingly found that the concentration of glial-derived neurotrophic factor (GDNF) was significantly increased in the sciatic nerves in mice treated with ASC. Since no detectable levels of GDNF were observed in ASC cultures, we hypothesize that ASC induced the local production of GDNF by Schwann cells. In conclusion, we show that systemically injected ASC have a clear therapeutic potential in an acute model of axonal damage. Among the possible mechanisms promoting nerve regeneration, our results rule out a process of trans-differentiation and rather suggest the relevance of a bystander effect, including the production of in situ molecules, which, directly or indirectly through a cross-talk with local glial cells, may modulate the local environment with the down-regulation of inflammation and the promotion of axonal regeneration.
间充质干细胞（MSCs）在神经组织工程中代表一种有前途的治疗方法。迄今为止，MSC 在损伤神经中的局部植入是唯一使用的给药途径。在多个损伤部位的情况下，建议使用能够到达受损神经的细胞进行全身给药。在这方面，我们发现，在坐骨神经挤压损伤后 1 周，即急性轴突损伤的小鼠模型中，静脉内给予脂肪来源的 MSC（ASC），可显著加速功能恢复。来自 ASC 治疗小鼠的坐骨神经显示存在数量有限的未分化 ASC，同时纤维发芽显著改善，炎症浸润减少，持续 3 周。除了免疫调节作用外，我们的结果表明 ASC 可能有助于周围神经再生，因为它们能够在培养物中产生神经保护因子，如胰岛素样生长因子 I、脑源性神经营养因子或碱性成纤维细胞生长因子。除了这种体外产生外，我们还发现有趣的是，在接受 ASC 治疗的小鼠的坐骨神经中，胶质衍生的神经营养因子（GDNF）的浓度显着增加。由于在 ASC 培养物中未检测到 GDNF 的可检测水平，我们假设 ASC 通过施万细胞诱导 GDNF 的局部产生。总之，我们表明，系统注射的 ASC 在急性轴突损伤模型中具有明确的治疗潜力。在促进神经再生的可能机制中，我们的结果排除了转分化过程，而是表明旁观者效应的相关性，包括原位分子的产生，这些分子直接或间接地通过与局部神经胶质细胞的串扰，可能通过下调炎症和促进轴突再生来调节局部环境。
