PDF(Pubmed)
Abstract：
Adult tissue stem cells contribute to tissue homeostasis and repair but the long-lived neurons in the human adult cerebral cortex are not replaced, despite evidence for a limited regenerative response. However, the adult cortex contains a population of proliferating oligodendrocyte progenitor cells (OPCs). We examined the capacity of rat cortical OPCs to be re-specified to a neuronal lineage both in vitro and in vivo. Expressing the developmental transcription factor Neurogenin2 (Ngn2) in OPCs isolated from adult rat cortex resulted in their expression of early neuronal lineage markers and genes while downregulating expression of OPC markers and genes. Ngn2 induced progression through a neuronal lineage to express mature neuronal markers and functional activity as glutamatergic neurons. In vivo retroviral gene delivery of Ngn2 to naive adult rat cortex ensured restricted targeting to proliferating OPCs. Ngn2 expression in OPCs resulted in their lineage re-specification and transition through an immature neuronal morphology into mature pyramidal cortical neurons with spiny dendrites, axons, synaptic contacts, and subtype specification matching local cytoarchitecture. Lineage re-specification of rat cortical OPCs occurred without prior injury, demonstrating these glial progenitor cells need not be put into a reactive state to achieve lineage reprogramming. These results show it may be feasible to precisely engineer additional neurons directly in adult cerebral cortex for experimental study or potentially for therapeutic use to modify dysfunctional or damaged circuitry.
摘要：
成年组织干细胞有助于组织稳态和修复，但人类成年大脑皮层中的长寿命神经元没有被取代，尽管有证据表明再生反应有限。然而,成人皮质含有一群增殖的少突胶质细胞祖细胞(OPCs)。我们在体外和体内检查了大鼠皮质OPCs被重新指定为神经元谱系的能力。在从成年大鼠皮质分离的OPCs中表达发育转录因子Neurogenin2（Ngn2）导致它们表达早期神经元谱系标记和基因，同时下调OPC标记和基因的表达。Ngn2通过神经元谱系诱导进展以表达成熟的神经元标记和作为谷氨酸能神经元的功能活性。将Ngn2体内逆转录病毒基因递送到幼稚的成年大鼠皮层确保了对增殖的OPC的有限靶向。OPCs中Ngn2的表达导致其谱系重新规范，并通过未成熟的神经元形态过渡到具有多刺树突的成熟锥体细胞皮层神经元，轴突,突触接触，和与局部细胞结构匹配的亚型规格。大鼠皮质OPCs的谱系重新规范发生，没有先前的损伤，证明这些神经胶质祖细胞不需要进入反应状态来实现谱系重编程。这些结果表明，直接在成人大脑皮层中精确设计额外的神经元以进行实验研究或潜在地用于治疗以修饰功能失调或受损的电路可能是可行的。
