Grafts of brain-derived neurotrophic factor and neurotrophin 3-transduced primate Schwann cells lead to functional recovery of the demyelinated mouse spinal cord
Grafts of brain-derived neurotrophic factor and neurotrophin 3-transduced primate Schwann cells lead to functional recovery of the demyelinated mouse spinal cord
复制标题
DOI：
10.1523/jneurosci.4890-04.2005
复制
发表时间：
2005-08-31
影响因子：
5.3
通讯作者：
Lachapelle, F
中科院分区：
文献类型：
--
作者：
Girard, C;Bemelmans, AP;Lachapelle, F
实验研究提供了压倒性的证据，证明髓鞘形成细胞的移植在CNS中实现有效的髓鞘再生。在细胞候选者中，许旺细胞可用于自体移植以确保损伤的稳健髓鞘再生并在CNS中递送治疗因子。在本研究中，表达绿色荧光蛋白（GFP）的猕猴Schwann细胞感染了人类免疫缺陷病毒衍生的载体，过度表达脑源性神经营养因子（BDNF）或神经营养因子3（NT-3），两种神经营养因子，也调节神经胶质细胞生物学。通过ELISA评估转基因雪旺细胞分泌生长因子的能力，并显示在转导的猕猴雪旺细胞上清液中BDNF和NT-3分别增加了35倍和62倍。BDNF和NT-3转导的雪旺细胞的条件培养基减少雪旺细胞增殖，并有利于它们在体外的分化。将转基因细胞移植到成年裸鼠脱髓鞘的脊髓中。两种行为学检测表明，NT-3和BDNF转导的雪旺细胞比GFP转导的雪旺细胞促进更快和更强的功能恢复。形态学分析表明，功能恢复与增强的增殖和分化的居民少突胶质细胞祖细胞和增强的少突胶质细胞和雪旺细胞分化。此外，NT-3转导的雪旺细胞提供神经保护和减少星形胶质细胞增生。这些结果强调了结合神经保护和髓鞘形成细胞的活化以恢复CNS脱髓鞘疾病中改变的功能的潜在治疗益处。
Experimental studies provided overwhelming proof that transplants of myelin-forming cells achieve efficient remyelination in the CNS. Among cellular candidates, Schwann cells can be used for autologous transplantation to ensure robust remyelination of lesions and to deliver therapeutic factors in the CNS. In the present study, macaque Schwann cells expressing green fluorescent protein (GFP) were infected with human immunodeficiency virus-derived vectors overexpressing brain-derived neurotrophic factor ( BDNF) or Neurotrophin 3 (NT-3), two neurotrophins that also modulate glial cell biology. The ability of transgenic Schwann cells to secrete growth factors was assessed by ELISA and showed 35- and 62-fold increases in BDNF and NT-3, respectively, in transduced macaque Schwann cell supernatants. Conditioned media of BDNF- and NT-3-transduced Schwann cells reduced Schwann cell proliferation and favored their differentiation in vitro. Transgenic cells were grafted in demyelinated spinal cords of adult nude mice. Two behavioral assays showed that NT-3- and BDNF-transduced Schwann cells promoted faster and stronger functional recovery than GFP-transduced Schwann cells. Morphological analysis indicated that functional recovery correlated with enhanced proliferation and differentiation of resident oligodendrocyte progenitors and enhanced oligodendrocyte and Schwann cell differentiation. Moreover, NT-3-transduced Schwann cells provided neuroprotection and reduced astrogliosis. These results underline the potential therapeutic benefit of combining neuroprotection and activation of myelin-forming cells to restore altered functions in demyelinating diseases of the CNS.