In vivo reprogramming of NG2 glia for neurogenesis

神经元丢失是神经损伤或变性的常见结果。一个根本但尚未解决的挑战是如何 恢复失去的神经元，修复成人中枢神经系统的神经回路。以干细胞为基础 移植在免疫兼容性、神经元存活和功能整合方面有局限性；它有 肿瘤发生的可能性。这项提案的长期目标是定义创新的再生战略 通过使用患者自己的疤痕形成细胞，而不是细胞移植。对受伤或神经损伤的反应 变性时，胶质细胞变得活跃、增殖并形成疤痕。疤痕形成最初的好处是 通过作为一种物理和化学物质限制损伤，但最终对神经再生有害 轴突再生和生长的障碍。我们先前的研究表明，反应性星形胶质细胞可以在体内 重新编程为可扩展的神经前体细胞，这可以进一步在成年中枢产生成熟神经元 神经系统。目前的提案将专注于NG2胶质细胞，这是胶质疤痕的另一个主要组成部分。我们的 初步数据表明，它们可以在体内重新编程，成为神经源性的。我们在此提议 确定成人NG2胶质细胞重编程过程的分子和细胞机制 老鼠。我们还将检测从NG2神经胶质细胞诱导的神经元的兴奋性和突触整合。 最后，我们将研究这些新产生的神经元在小鼠神经模型中的生物学功能。 受伤。这项工作的结果可能导致基于范式转换和再生的神经治疗策略 损伤和退化。

Neuron loss is a frequent result of neural injury or degeneration. A fundamental but unresolved challenge is how to restore the lost neurons and repair the neural circuits in the adult central nervous system. Stem cell-based transplantation has limitations on immune compatibility, neuronal survival, and functional integration; and it has the potential for tumorigenesis. The long-term goal of this proposal is to define innovative regenerative strategies by using a patient’s own scar-forming cells without cell transplantation. In response to injury or neural degeneration, glial cells become reactive, proliferate, and form scars. Scar formation is initially beneficial by restricting damage but ultimately detrimental to neural regeneration through acting as a physical and chemical barrier to axonal regeneration and growth. Our prior research showed that reactive astrocytes can be in vivo reprogrammed to expandable neural progenitors, which can further produce mature neurons in the adult central nervous system. The current proposal will focus on NG2 glia, another major component of the glial scar. Our preliminary data indicate that they can be in vivo reprogrammed to become neurogenic. We here propose to determine the molecular and cellular mechanisms underlying the reprogramming process of NG2 glia in adult mouse. We will also examine the excitability and synaptic integrations of the induced neurons from NG2 glia. Finally, we will investigate the biological function of these newly generated neurons in a mouse model of neural injury. Results from this work may lead to paradigm-shifting regeneration-based therapeutic strategies for neural injury and degeneration.