School of Biological and Health Systems Engineering, Arizona State University, P.O. Box 879709, Tempe, AZ 85287-9709, USA.
School of Biological and Health Systems Engineering, Arizona State University, P.O. Box 879709, Tempe, AZ 85287-9709, USA.
Biomaterials. 2014 Mar;35(10):3263-72. doi: 10.1016/j.biomaterials.2013.12.102. Epub 2014 Jan 15.
The consequences of central nervous system injury are far-reaching and debilitating and, while an endogenous repair response to neural injury has been observed in recent years, the mechanisms behind this response remain unclear. Neural progenitor/stem cell (NPSC) migration to the site of injury from the neural stem cell niches (e.g. subventricular zone and hippocampus) has been observed to be vasophilic in nature. While the chemotactic stimuli directing NPSC homing to injury is not well established, it is thought to be due in part to an increasing gradient of chemotactic cytokines, such as stromal cell-derived factor 1α (SDF-1α). Based on these recent findings, we hypothesize that critical crosstalk between SDF-1α and the extracellular matrix (ECM) drives injury-induced NPSC behavior. In this study, we investigated the effect of SDF-1α and ECM substrates (Matrigel, laminin, and vitronectin) on the migration, differentiation, and proliferation of NPSCs in vitro using standard assays. The results demonstrated that SDF-1α and laminin-based ECM (Matrigel and laminin) significantly and synergistically enhanced NPSC migration and acute neuronal differentiation. These effects were significantly attenuated with the addition of AMD3100 (an antagonist against the SDF-1α receptor, CXCR4). SDF-1α alone significantly increased NPSC proliferation regardless of ECM substrate, however no synergy was observed between SDF-1α and the ECM. These results serve to elucidate the relationship between adhesive and soluble signaling factors of interest and their effect on NPSC behavior following neural injury. Furthermore, these results better inform the next generation of biomaterials aimed at stimulating endogenous neural regeneration for neural injury and neurodegenerative diseases.
中枢神经系统损伤的后果是深远而衰弱的，尽管近年来观察到了内源性神经损伤修复反应，但这种反应的机制仍不清楚。已经观察到神经祖细胞/干细胞（NPSC）从神经干细胞巢（例如侧脑室下区和海马体）迁移到损伤部位是嗜血管的。虽然指导 NPSC 归巢到损伤部位的趋化刺激物尚未得到很好的确定，但据认为部分原因是趋化细胞因子（如基质细胞衍生因子 1α（SDF-1α））的浓度梯度增加。基于这些最近的发现，我们假设 SDF-1α 和细胞外基质（ECM）之间的关键串扰驱动损伤诱导的 NPSC 行为。在这项研究中，我们使用标准测定法研究了 SDF-1α 和 ECM 底物（Matrigel、层粘连蛋白和纤连蛋白）对 NPSCs 在体外迁移、分化和增殖的影响。结果表明，SDF-1α 和基于 ECM 的层粘连蛋白（Matrigel 和层粘连蛋白）显著协同增强了 NPSC 的迁移和急性神经元分化。在用 AMD3100（SDF-1α 受体 CXCR4 的拮抗剂）添加后，这些作用显著减弱。SDF-1α 单独使用可显著增加 NPSC 的增殖，而与 ECM 底物无关，但 SDF-1α 与 ECM 之间未观察到协同作用。这些结果阐明了感兴趣的粘附和可溶性信号因子之间的关系及其对神经损伤后 NPSC 行为的影响。此外，这些结果为旨在刺激内源性神经再生以治疗神经损伤和神经退行性疾病的下一代生物材料提供了更好的信息。
