Mapping hESC neuronal lineage programming

描述（由申请人提供）：来源于内细胞团（ICM）的人胚胎干细胞（hESC）为人类发育提供了模型系统，并为细胞基础治疗提供了潜在的无限移植材料来源。hESCs的多能性意味着这种细胞在组织和功能修复方面具有巨大的潜力，同时它也为从hESCs中产生大量统一的替代细胞用于治疗疾病提供了一种实用的方法。将hESC有效地控制分化为功能谱系一直是实现hESC治疗前景的艰巨挑战之一，需要对指导hESC分化程序的分子和细胞线索有深入的了解。以前的hESC分化过程很大程度上依赖于多系聚集体的形成，其中只有一小部分追求给定的表型，部分原因是人们一直认为组织和器官系统来自三个胚胎胚层。然而，神经系统和心脏是第一批由ICM细胞形成的组织和器官系统。可以推断，早期胚胎的神经和心脏谱系可能直接来自多能hESCs。因此，我假设一个最小的基本培养系统将提供足够的信号分子来指定多能hESCs直接和专一地分化为神经外胚层和心内胚层，神经系统和心脏分别从神经外胚层和心内胚层进化而来。本项目将重点研究hESC神经分化程序。这一建议为直接诱导多能hESCs进入丰富的神经限制子代细胞治疗提供了一种新的方法，同时也为研究人类胚胎神经发生的分子控制提供了一种有效的体外模型系统。我们的初步数据支持了这个项目的可行性。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。

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.