Mapping hESC neuronal lineage programming

描述（由申请人提供）：人胚胎干细胞（hESC）来源于内细胞团（ICM），为人类发育提供了模型系统，也为基于细胞的治疗提供了潜在的无限移植材料来源。hESC的多分化意味着这些细胞在组织和功能恢复方面的巨大潜力，而它已经腾出了一种实用的方法来从hESC产生大量均匀的替代细胞用于治疗疾病。hESC有效地受控分化为功能谱系一直是实现hESC的治疗前景的艰巨挑战之一，并且需要彻底理解指导hESC分化程序的分子和细胞线索。以前的hESC分化程序主要依赖于多谱系聚集体的形成，其中只有一小部分追求给定的表型，部分原因是假设组织和器官系统来自三个胚胎胚层。然而，神经系统和心脏是由ICM细胞形成的第一个组织和器官系统。可以推断，早期胚胎神经和心脏谱系的特化可能直接发生于多能hESC。因此，我假设，一个最小的基本文化系统将使信号分子足以指定多能hESCs分化直接和排他性的神经外胚层和心中胚层从神经系统和心脏的发展，分别。该项目将集中于揭示hESC神经分化程序。这一建议允许一种新的方法，用于直接诱导多能hESC专门进入一个丰富的收集的神经限制性后代的细胞为基础的治疗，以及一个有效的体外模型系统的发展，以调查在人类胚胎神经发生的分子控制。我们的初步数据支持这个项目的可行性。这些研究将极大地提高我们操纵hESC分化的能力，并有助于制定预防和治疗疾病的策略。该项目带来的突破将对生物医学科学产生重大影响。 公共卫生相关性：这项拟议的研究将揭示控制人类发育中特定体细胞表型形成的生物学途径和分子靶点，从而有助于制定更有效的途径，从人胚胎干细胞（hESC）中获得具有神经元潜能的体干细胞的最佳来源，用于基于细胞的治疗。

DESCRIPTION (provided by applicant): The human embryonic stem cell (hESC), derived from the inner cell mass (ICM), offers both a model system for human development and a potentially unlimited source of graft material for cell-based therapies. The pluripotence of hESCs implies such cells' tremendous potential for tissue and function restoration, whereas it has vacated a practical approach to generate a large supply of uniform replacement cells from hESCs for treating diseases. Controlled differentiation of hESCs effectively into functional lineages has been one of the daunting challenges for fulfilling the therapeutic promise of hESCs and requires a through understanding of the molecular and cellular cues that direct hESC differentiation programs. Previous hESC differentiation procedures largely rely on the formation of multi-lineage aggregates where only a small fraction pursues a given phenotype, in part because it has been assumed that tissue and organ systems arise from the three embryonic germ layers. However, the nervous system and the heart are among the first tissue and organ systems formed from the cells of the ICM. It is deducible that the specification of early embryonic neural and cardiac lineages may occur directly from pluripotent hESCs. Therefore, I hypothesize that a minimal essential culture system will render signal molecules sufficient to specify pluripotent hESCs differentiate directly and exclusively into neuroectoderm and cardiomesoderm from where the nervous system and the heart evolve, respectively. This project will focus on uncovering hESC neural differentiation programs. This proposal allows a novel approach for direct induction of pluripotent hESCs exclusively into a rich collection of neural-restricted progenies for cell-based therapies as well as the development of an effective in vitro model system to investigate molecular controls in human embryonic neurogenesis. The feasibility of this project is supported by our preliminary data. These studies will tremendously improve our ability to manipulate hESC differentiation and help develop strategies for preventing and treating diseases. The breakthrough brought by this project will have significant impact on biomedical sciences. Public Health Relevance: This proposed research will reveal the biological pathways and molecular targets that control the formation of particular somatic phenotypes in human development, thereby aid the formulation of more efficient routes to derive an optimal source of somatic stem cells with neuronal potential from human embryonic stem cells (hESCs) for cell-based therapies.