REGULATION OF POSTNATAL CORTICAL MULTIPOTENT PROGENITORS

产后皮质多能祖细胞的调节

• 批准号: 6394170
• 负责人: Mark F Mehler
• 金额: $ 29.61万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-04-01 至 2003-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6394170
• 关键词: cell cell interaction; cell differentiation; cell growth regulation; cell proliferation; cell transplantation; cerebral cortex; developmental neurobiology; epidermal growth factor; fluorescence microscopy; glia; immunocytochemistry; laboratory rat; neurogenesis; neurons; neurotrophic factors; newborn animals; oligodendroglia; stem cells

We have isolated multipotent progenitor cells from the cerebral cortex independent of periventricular generative zones during the peak period of early postnatal gliogenesis. These progenitor species undergo cellular expansion and self-renewal in vitro in response to epidermal growth factor and can generate neurons and glia, including myelin protein-expressing oligodendrocytes. Glial progenitors derived from these multipotent progenitors express the neurotrophin-3 receptor, trkC, and application of neurotrophin-3 selectively promotes the expansion of oligodendrocyte progenitors that require additional environmental signals (ciliary neurotrophic factor, CNTF) for oligodendrocyte differentiation. Neurotrophin-3 can also induce the expression of the CNTFalpha receptor on glial progenitors derived from cortical multipotent cells, while bone morphogenetic proteins promote the generation of astrocytes and induce the expression of trkC on these progenitor species. In preliminary in vivo studies, we have also shown that transplanted cortical multipotent cells can undergo cellular expansion and give rise to glial and neuronal progeny. In addition, glial progenitors isolated from these multipotent cells proliferate in vivo and give rise to oligodendrocytes and astrocytes. Cortical injury enhances progenitor cell expansion and differentiation. In vitro analysis: 1. To define the cellular properties of epidermal growth factor-responsive cortical multipotent progenitors and their progeny: A. Do these progenitors undergo long-term self-renewal? B. What is the composition of neural lineage species derived from these multipotent cells? C. What are the cellular actions of neurotrophin-3 on oligodendroglial and astroglial development from glial progenitors derived from these multipotent cells? In vivo analysis: 2. To define the presence of appropriate early postnatal microenvironmental signals for cortical progenitor cell development: A. Are the cellular profiles of progenitor expansion, lineage restriction and differentiation equivalent in vitro and in vivo? B. Are glial-restricted progeny bipotent in vivo? C. Do different areas of the CNS neuraxis promote distinct progenitor cell response profiles? These studies will further our understanding of early progenitor cell regulatory events in neural lineage development during normal mammalian cerebral cortical maturation, identify pathologic mechanisms underlying a range of genetic and acquired neurologic disorders, and promote the development of novel regenerative strategies.

我们从大脑皮层中分离出了多能祖细胞 在高峰期不依赖于室周生成区 出生后早期胶质细胞的形成 这些祖先物种经历了 细胞增殖和自我更新在体外响应表皮 生长因子，可以产生神经元和神经胶质，包括髓鞘 表达蛋白质的少突胶质细胞。胶质祖细胞来源于 这些多能祖细胞表达神经营养素-3受体，trkC， 神经营养素-3的应用选择性地促进了 少突胶质细胞祖细胞需要额外的环境 信号（睫状神经营养因子，CNTF）的少突胶质细胞 分化 神经营养素-3还可以诱导 皮层神经胶质祖细胞上的CNTF α受体 多能细胞，而骨形态发生蛋白则促进多能细胞 星形胶质细胞的产生并诱导这些细胞上trkC的表达 祖先物种 在初步的体内研究中，我们还表明， 移植的皮层多能细胞可以经历细胞 扩增并产生神经胶质和神经元后代。 此外，本发明还提供了一种方法， 从这些多能细胞中分离的神经胶质祖细胞增殖， 体内并产生少突胶质细胞和星形胶质细胞。 皮层损伤 增强祖细胞扩增和分化。体外 分析：1.来定义表皮生长的细胞特性 因子响应性皮质多能祖细胞及其后代： A. 这些祖细胞会进行长期的自我更新吗？ B。 是什么 神经谱系物种的组成来源于这些多能 细胞？ C. 神经营养素-3在细胞内的作用是什么？ 少突胶质细胞和星形胶质细胞从胶质祖细胞发育 从这些多能细胞中提取的体内分析：2. 以限定 适当的早期出生后微环境信号的存在 皮质祖细胞发育：A. 是细胞分布图 祖先的扩张，谱系的限制和分化 体外和体内等效？ B。 是胶质细胞限制的后代 体内双能性 C. 中枢神经系统轴突的不同区域 不同的祖细胞反应谱 这些研究将进一步加深我们对早期祖细胞 正常哺乳动物神经谱系发育中的调节事件 大脑皮层成熟，确定病理机制， 一系列遗传性和获得性神经系统疾病，并促进 开发新的再生策略。