Olig 2 Lineage Cells Derived From ES Cells

来自 ES 细胞的 Olig 2 谱系细胞

• 批准号: 6774425
• 负责人: DAVID I GOTTLIEB
• 金额: $ 34.16万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-03-01 至 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6774425
• 关键词: alternatives to animals in research; biological signal transduction; cell cycle; cell differentiation; cell growth regulation; cell population study; cell proliferation; developmental neurobiology; embryonic stem cell; flow cytometry; gene expression; gene expression profiling; gene targeting; genetic manipulation; genetic regulation; laboratory mouse; laboratory rat; model; motor neurons; neurogenesis; oligodendroglia; retinoate; tissue /cell culture; transcription factor

The long-term goal of this research is two-fold. One is to gain insights into the mechanisms that control fate choice in the early developing nervous system. The principal tool is ES cells differentiated in culture to produce a model of normal CNS development. The model is powerful because large numbers of cells are produced and because gone targeting and other genetic manipulations are feasible. Using the advantages of this model we will investigate how early neural precursor cells choose a fate defined by expression of the Olig2 gene. Cells from this pathway eventually differentiate into motor neurons and oligodendrocytes. Retinoic acid and sonic hedgehog interact to specify na'ive cells to follow this fate. We will learn how these 2 pathways interact. Specified cells are capable of cell division. We have discovered how to induce dividing cells to undergo long-term division. Even though they divide continuously the cells keep their identity as members of the Olig2 lineage. Our working hypothesis is that normal early neural stem cells are indeed capable of sustained division. If true, this will provide large numbers of specified neural stem cells for many applications. The final stage of stem cell life is differentiation. We will investigate signals that are responsible for differentiation of Olig2 pathway cells. We have already discovered how to efficiently differentiate these cells into astrocytes and oligodendrocytes and will extend this work to neurons. The second long-term goal is to harness the potential that ES cells have for neural transplantation. While the potential is real, practical application demands major advances in basic understanding. It is theoretically possible to direct ES cells to coordinately differentiate into any single type of neural cell. Achievement of this goal even for a few cell lineages would open up new opportunities in transplantation research. Results of this project will provide proof-of-principle for this idea. A combination of instructive and selective strategies is being applied to the goal of getting pure populations. Cells from each stage of the Olig2 lineage will be available in large numbers and at high purity. Lessons learned from this lineage will be applicable to others. One strong possibility is that genetically engineered cells will be most efficacious in transplantation. The ES cell-based system is ideally suited to providing genetically engineered cells.

这项研究的长期目标是双重的。一个是深入了解在早期发育的神经系统中控制命运选择的机制。主要工具是在培养中分化的ES细胞，以产生正常CNS发育的模型。该模型是强大的，因为产生了大量的细胞，因为去靶向和其他遗传操作是可行的。利用该模型的优势，我们将研究早期神经前体细胞如何选择由Olig 2基因表达定义的命运。来自该途径的细胞最终分化为运动神经元和少突胶质细胞。视黄酸和音速刺猬相互作用，指定幼稚细胞遵循这一命运。我们将学习如何这两个 路径相互作用。特定的细胞能够进行细胞分裂。我们已经发现了如何诱导分裂细胞进行长期分裂。尽管它们不断分裂，但细胞仍保持其作为Olig2谱系成员的身份。我们的工作假设是，正常的早期神经干细胞确实能够持续分裂。如果是真的，这将为许多应用提供大量特定的神经干细胞。干细胞生命的最后阶段是分化。我们将研究负责Olig2途径细胞分化的信号。我们已经发现了如何有效地将这些细胞分化为星形胶质细胞和少突胶质细胞，并将这项工作扩展到神经元。第二个长期目标是利用ES细胞用于神经移植的潜力。而 潜力是真实的，实际应用需要在基本认识方面取得重大进展。从理论上讲，指导ES细胞协调分化为任何单一类型的神经细胞是可能的。即使是在少数细胞谱系中实现这一目标，也将为移植研究开辟新的机会。该项目的结果将为这一想法提供原理证明。指导性和选择性策略的结合正在被应用于获得纯种群的目标。来自Olig2谱系的每个阶段的细胞将以大量和高纯度获得。从这一传承中吸取的经验教训将适用于其他传承。一个很大的可能性是基因工程细胞在移植中将是最有效的。的ES 基于细胞的系统理想地适合于提供基因工程细胞。