Department of Neurology, The Agnes Ginges Center for Human Neurogenetics, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel.
J Neurosci. 2009 Dec 16;29(50):15694-702. doi: 10.1523/JNEUROSCI.3364-09.2009.
In multiple sclerosis lesions resident oligodendrocyte progenitor cells (OPCs) are present, but fail to remyelinate. In the current study we examined whether neural precursor cell (NPC) transplantation can facilitate host brain-derived remyelination. We used the chronic cuprizone-induced demyelination model in aged mice, in which slow remyelination follows cuprizone removal. NPCs were transplanted to the lateral ventricles (intracerebroventricular) of cuprizone-induced demyelinated brains. In this experimental setup, transplanted cells remained mostly in the periventricular area in an undifferentiated state. The extent of demyelination, remyelination, and proliferation of host brain regenerative cell population were examined at 1 week posttransplantation in the splenium of the corpus callosum, which was devoid of any transplanted cells. Transplantation of NPCs, but not of control, human embryonic kidney cells, significantly enhanced remyelination compared with sham-operated mice. Remyelination was performed exclusively by host brain OPCs. The proregenerative effect of transplanted NPCs was related to an increase in the proliferation of host brain OPCs. To examine the mechanism that underlies the proregenerative effect of NPCs in vitro, we used an NPC-OPC coculture system. These experiments indicated that NPCs induced the proliferation of OPCs and facilitated their differentiation into mature oligodendrocytes. The mitogenic effect of NPCs was mediated by platelet-derived growth factor-AA and fibroblast growth factor-2. In conclusion, NPC transplantation enhances host-derived myelin regeneration following chronic demyelination. This trophic effect may stimulate resident OPCs to overcome the remyelination failure in multiple sclerosis.
在多发性硬化症病变中，存在着固有少突胶质前体细胞（OPC），但它们未能进行髓鞘修复。在本研究中，我们研究了神经前体细胞（NPC）移植是否能促进宿主脑源性髓鞘修复。我们使用了慢性铜缺乏诱导的脱髓鞘模型，在该模型中，铜缺乏去除后髓鞘修复缓慢。将 NPC 移植到侧脑室（脑室内）的脱髓鞘大脑中。在这种实验设置中，移植细胞大多保持在未分化状态的脑室周围区。在移植后 1 周，在胼胝体体部的体部检查脱髓鞘、髓鞘修复和宿主脑再生细胞群体的增殖程度，该区域没有任何移植细胞。与假手术组相比，NPC 移植而非对照的人胚胎肾细胞移植显著增强了髓鞘修复。髓鞘修复完全由宿主脑 OPC 完成。移植 NPC 的促再生作用与宿主脑 OPC 增殖增加有关。为了研究 NPC 在体外的促再生作用的机制，我们使用了 NPC-OPC 共培养系统。这些实验表明，NPC 诱导 OPC 的增殖，并促进其分化为成熟的少突胶质细胞。NPC 的有丝分裂作用是由血小板衍生生长因子-AA 和成纤维细胞生长因子-2介导的。总之，NPC 移植增强了慢性脱髓鞘后宿主来源的髓鞘再生。这种营养作用可能刺激固有 OPC 克服多发性硬化症中的髓鞘修复失败。
