Liu G, Anisman H, Bobyn J, Hayley S
Department of Neuroscience, Carleton University, 327 Life Sciences Research Building, 1125 Colonel By Drive, Ottawa, ON, K1S 5B6, Canada.
Mol Neurobiol. 2014 Oct;50(2):673-84. doi: 10.1007/s12035-014-8680-2. Epub 2014 Mar 28.
There are currently no known treatment options that actually halt or permanently reverse the pathology evident in any neurodegenerative condition. Arguably, one of the most promising avenues for creating viable neuronal treatments could involve the combined use of cell replacement and gene therapy. Given the complexity of the neurodegenerative process, it stands to reason that adequate therapy should involve not only the replacement of loss neurons/synapses but also the interruption of multiple pro-death pathways. Thus, we propose the use of stem cells that are tailored to express specific trophic factors, thereby potentially encouraging synergistic effects between the stem cell properties and those of the trophic factors. The trophic factors, brain-derived neurotropic factor (BDNF), glial cell-derived neurotropic factor (GDNF), fibroblast growth factor (FGF) 2, and insulin-like growth factor (IGF) 1, in particular, have demonstrated neuroprotective actions in a number of animal models. Importantly, we use a nonviral approach, thereby minimizing the potential risk for DNA integration and tumor formation. The present study involved the development of a nonviral reprogramming system to transform adult mature mouse fibroblasts into progressive stages of cell development. We also tailored these stem cells to individually express each of the trophic factors, including BDNF, GDNF, FGF2, and IGF1. Significantly, central infusion of BDNF-expressing stem cells prevented the in vivo loss of neurons associated with infusion of the endotoxin, lipopolysaccharide (LPS). This is particularly important in light of the role of inflammatory processes that are posited to play in virtually all neurodegenerative states. Hence, the present results support the utility of using combined gene and cell-targeting approaches for neuronal pathology.
目前尚无已知的治疗方法能够真正阻止或永久逆转任何神经退行性疾病中明显的病理变化。可以说，开发可行的神经元治疗方法最有前景的途径之一可能涉及细胞替代和基因治疗的联合使用。鉴于神经退行性过程的复杂性，合理的治疗不仅应包括替代丢失的神经元/突触，还应包括中断多种促死亡途径。因此，我们建议使用经过定制以表达特定营养因子的干细胞，从而有可能促进干细胞特性与营养因子特性之间的协同效应。特别是脑源性神经营养因子（BDNF）、胶质细胞源性神经营养因子（GDNF）、成纤维细胞生长因子（FGF）2和胰岛素样生长因子（IGF）1等营养因子，已在许多动物模型中显示出神经保护作用。重要的是，我们采用非病毒方法，从而将DNA整合和肿瘤形成的潜在风险降至最低。本研究涉及开发一种非病毒重编程系统，将成年成熟小鼠成纤维细胞转化为细胞发育的进展阶段。我们还对这些干细胞进行定制，使其分别表达每种营养因子，包括BDNF、GDNF、FGF2和IGF1。值得注意的是，向中枢注入表达BDNF的干细胞可防止与注入内毒素脂多糖（LPS）相关的体内神经元丢失。鉴于炎症过程在几乎所有神经退行性疾病状态中所起的作用，这一点尤为重要。因此，本研究结果支持将基因和细胞靶向联合方法用于治疗神经元病理的实用性。
