Lepore A C, Neuhuber B, Connors T M, Han S S W, Liu Y, Daniels M P, Rao M S, Fischer I
Department of Neurobiology and Anatomy, 2900 Queen Lane, Drexel University College of Medicine, Philadelphia, PA 19129, USA.
Neuroscience. 2006 May 12;139(2):513-30. doi: 10.1016/j.neuroscience.2005.12.043. Epub 2006 Feb 3.
Successful strategies for transplantation of neural precursor cells for replacement of lost or dysfunctional CNS cells require long-term survival of grafted cells and integration with the host system, potentially for the life of the recipient. It is also important to demonstrate that transplants do not result in adverse outcomes. Few studies have examined the long-term properties of transplanted neural precursor cells in the CNS, particularly in non-neurogenic regions of the adult. The aim of the present study was to extensively characterize the fate of defined populations of neural precursor cells following transplantation into the developing and adult CNS (brain and spinal cord) for up to 15 months, including integration of graft-derived neurons with the host. Specifically, we employed neuronal-restricted precursors and glial-restricted precursors, which represent neural precursor cells with lineage restrictions for neuronal and glial fate, respectively. Transplanted cells were prepared from embryonic day-13.5 fetal spinal cord of transgenic donor rats that express the marker gene human placental alkaline phosphatase to achieve stable and reliable graft tracking. We found that in both developing and adult CNS grafted cells showed long-term survival, morphological maturation, extensive distribution and differentiation into all mature CNS cell types (neurons, astrocytes and oligodendrocytes). Graft-derived neurons also formed synapses, as identified by electron microscopy, suggesting that transplanted neural precursor cells integrated with adult CNS. Furthermore, grafts did not result in any apparent deleterious outcomes. We did not detect tumor formation, cells did not localize to unwanted locations and no pronounced immune response was present at the graft sites. The long-term stability of neuronal-restricted precursors and glial-restricted precursors and the lack of adverse effects suggest that transplantation of lineage-restricted neural precursor cells can serve as an effective and safe replacement therapy for CNS injury and degeneration.
用于替代丢失或功能失调的中枢神经系统（CNS）细胞的神经前体细胞移植的成功策略，需要移植细胞的长期存活以及与宿主系统整合，这可能贯穿受体的一生。同样重要的是要证明移植不会导致不良后果。很少有研究考察过移植到中枢神经系统中的神经前体细胞的长期特性，尤其是在成体的非神经源性区域。本研究的目的是广泛地描述特定群体的神经前体细胞在移植到发育中和成年的中枢神经系统（脑和脊髓）长达15个月后的命运，包括移植来源的神经元与宿主的整合。具体而言，我们使用了神经元限制性前体细胞和胶质细胞限制性前体细胞，它们分别代表对神经元和胶质细胞命运具有谱系限制的神经前体细胞。移植细胞取自表达标记基因人胎盘碱性磷酸酶的转基因供体大鼠胚胎第13.5天的胎儿脊髓，以实现稳定可靠的移植追踪。我们发现，在发育中和成年的中枢神经系统中，移植细胞均表现出长期存活、形态成熟、广泛分布并分化为所有成熟的中枢神经系统细胞类型（神经元、星形胶质细胞和少突胶质细胞）。通过电子显微镜鉴定，移植来源的神经元还形成了突触，这表明移植的神经前体细胞与成年中枢神经系统整合。此外，移植并未导致任何明显的有害后果。我们未检测到肿瘤形成，细胞未定位到不需要的位置，并且在移植部位没有明显的免疫反应。神经元限制性前体细胞和胶质细胞限制性前体细胞的长期稳定性以及缺乏不良影响表明，谱系限制性神经前体细胞移植可作为中枢神经系统损伤和退变的一种有效且安全的替代疗法。
