Olig 2 Lineage Cells Derived From ES Cells

来自 ES 细胞的 Olig 2 谱系细胞

• 批准号: 7217978
• 负责人: DAVID I GOTTLIEB
• 金额: $ 30.19万
• 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/7217978
• 关键词: Achievement; Antibodies; Astrocytes; BMP2 gene; BMP4; Basic Science; Biological Process; Cell Count; Cell Lineage; Cell Transplantation; Cell division; Cell physiology; Cells; Ciliary Neurotrophic Factor; Commit; Data; Development; EGF gene; ES Cell Line; Erinaceidae; FGF8 gene; Fibroblast Growth Factor 2; Fibroblast Growth Factor 8; Gene Expression; Gene Expression Profiling; Genes; Glial Differentiation; Goals; Green Fluorescent Proteins; In Vitro; Knock-in Mouse; Learning; Life; Maps; Measures; Mitogens; Modeling; Motor Neurons; Multipotent Stem Cells; Nervous system structure; Neuroglia; Neuronal Differentiation; Neurons; Numbers; Oligodendroglia; Pathway interactions; Platelet-Derived Growth Factor; Population; Protocols documentation; Reagent; Research; Reverse Transcriptase Polymerase Chain Reaction; SHH gene; Serum; Signal Transduction; Source; Specific qualifier value; Staging; Staining method; Stains; Stem cells; System; Testing; Time; To specify; Transplantation; Tretinoin; Work; autocrine; base; bone morphogenetic protein 4; embryonic stem cell; genetic manipulation; genetically modified cells; in vivo; insight; mRNA Expression; member; nerve stem cell; neurodevelopment; practical application; precursor cell; progenitor; receptor; relating to nervous system; research study; response; tool

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两个方面。一种是了解在早期发展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，以产生正常中枢神经系统发育模型。该模型之所以强大，是因为产生了大量细胞，并且靶向靶向和其他遗传操作是可行的。使用该模型的优点，我们将研究早期神经前体细胞如何选择由Olig2基因表达定义的命运。该途径的细胞最终分化为运动神经元和少突胶质细胞。视黄酸和声音刺猬相互作用以指定Na'ive细胞以遵循这种命运。我们将学习这两个 途径相互作用。指定的细胞能够分裂。我们发现如何诱导分裂细胞进行长期分裂。即使它们连续划分，细胞仍将其作为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。如果为true，这将为许多应用提供大量指定的神经干细胞。干细胞寿命的最后阶段是分化。我们将研究负责分化Olig2途径细胞的信号。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细胞对神经移植的潜力。而 潜力是真实的，实际的应用需要基本理解的重大进展。从理论上讲，可以指导ES细胞协同分化为任何单一类型的神经细胞。即使在一些细胞谱系中，实现这一目标也将为移植研究打开新的机会。该项目的结果将为这个想法提供原理证明。将启发性和选择性策略的结合用于获得纯粹人群的目标。来自Olig2谱系每个阶段的细胞将大量且纯度高。从这个血统中学到的教训将适用于其他人。一种强大的可能性是，基因工程的细胞在移植中最有效。 ES 基于细胞的系统非常适合提供基因工程的细胞。