Neurogenesis de novo in the adult central nervous system

描述(由申请人提供) 摘要：创伤、中风和神经退行性疾病会导致神经元丢失，从而导致发病率和死亡率。缓解这些情况的一个主要进步将是利用再生丢失神经元的能力。虽然神经干细胞(NSCs)和神经发生通常存在于成人脑中，但其稀缺性和局限性使其不足以再生。细胞移植是目前移植新的神经细胞的首选策略，但由于移植后细胞存活有限以及与功能神经网络的整合不佳，这种方法效率低且繁琐。在基于最新发现的一种非常新颖的成人神经发生研究方法中，我们假设内源性神经胶质细胞可以直接转化为神经源性神经干细胞，以便新生神经元重新填充受损的脑区。这一假设是基于我们对神经干细胞的一种重要核受体的广泛研究以及诱导多能干细胞(IPS)的最新进展。我们先前发现，核受体TLX不仅对成年神经发生是必要的，而且在培养中也足以将分化的星形胶质细胞转化为神经干细胞。尽管来自不同组织的体细胞可以被重新编程为iPS细胞，但目前还不清楚体细胞是否也可以直接诱导形成神经干细胞和神经元。通过转录重编程，我们建议将星形胶质细胞和小胶质细胞这两种在中枢神经系统损伤中增殖最多的胶质细胞转化为神经干细胞和神经元。利用TLX在培养细胞和转基因小鼠中的调控表达，我们将诱导星形胶质细胞成为增殖的、多潜能的神经干细胞，然后向神经元分化。此外，通过使用转录因子的组合，我们将在细胞培养和成年小鼠脑中直接将星形胶质细胞或小胶质细胞重新编程为神经干细胞。我们的长期目标是使用患者的内源性非神经细胞重新填充受损的中枢神经系统区域。 公共卫生相关性：创伤、中风或变性可导致中枢神经系统(CNS)的永久性损害，从而导致残疾和死亡。目前，中枢神经系统损伤患者的护理和治疗要求高、费用高。我们的研究重点是成人的神经发生，并采取了一种创新的方法来诱导成人中枢神经系统产生新的神经元，最终目标是利用患者的内源性细胞修复受损的中枢神经系统的功能。因此，我们的研究对公共卫生具有很高的相关性和重要意义。

DESCRIPTION (Provided by the applicant) Abstract: Trauma, stroke, and neurodegenerative disease result in neuronal loss, which leads to morbidity and mortality. A major advancement to mitigate these conditions would be to harness the ability to regenerate lost neurons. Although neural stem cells (NSCs) and neurogenesis normally exist in adult brain, the scarcity and restricted localization render them inadequate for regeneration. Cell transplantation is currently the strategy of choice to deliver new neuronal cells, but this approach is inefficient and cumbersome due to limited cell survival and poor integration into the functional neural networks following transplantation. In a highly novel approach to adult neurogenesis studies based on recent findings, we hypothesize that endogenous glial cells can be directly converted into neurogenic NSCs so that de novo-generated neurons will repopulate damaged brain regions. This hypothesis is based on our extensive studies using an essential nuclear receptor for NSCs and on the recent advancement of induced pluripotent stem (iPS) cells. We previously revealed that nuclear receptor TLX is not only essential for adult neurogenesis but is also sufficient to convert differentiated astrocytes into NSCs in culture. Although somatic cells from various tissues can be reprogrammed to iPS cells, it is not clear whether somatic cells can also be directly induced to form NSCs and neurons. Through transcriptional reprogramming, we propose to convert astrocytes and microglia, the two most proliferative glia cells during CNS damage, into NSCs and neurons. Using regulated expression of TLX in cultured cells and in transgenic mice, we will induce astrocytes to become proliferative, multipotent NSCs and then differentiate them into neurons. In addition, by using combinations of transcription factors, we will directly reprogram astrocytes or microglia to NSCs in cell culture and in adult mouse brains. Our long-term goal is to repopulate the damaged CNS regions using the patient's endogenous non-neuronal cells. Public Health Relevance: Trauma, stroke or degeneration can result in permanent damage to the central nervous system (CNS), which leads to disability and mortality. Currently, care and treatment of patients with CNS injury are demanding and extremely expensive. Our proposed research focuses on adult neurogenesis and takes an innovative approach to induce the production of new neurons in the adult CNS, with the ultimate goal of repairing the function of damaged CNS using endogenous cells from patients. Thus, our research is highly relevant and significant to public health.