Stem cells and phenotype specification in neural lineage development - Regulation of growth and differentiation in human stem cell systems

本提案中概述的实验将显着增强目前对人类神经发育中的谱系规范和细胞-细胞相互作用的了解。神经谱系（神经生成）的发展包含了许多高度精细的阶段和转变。主要的研究工作是针对多能干细胞（PSCs）分化成生物医学上相关的表型。然而，总的来说，我们对神经形态发生和表型规范的信号通路和调控网络的理解仍然非常有限。目前的PSCs定向分化方法导致不适当的表型和异质、控制不良的培养，这表明目前的体外方案忽视了细胞间相互作用的方面，以及它们与适当的模式、位置规范和形态发生的相关性。为了阐明这种自组织发育系统的细胞间通讯的本质，有必要研究神经表面分子和分泌因子及其各自在神经表型规范中的相互作用。我们假设对hpsc衍生的神经细胞之间通过各自的差异细胞表面特征与分泌因子/扩散形态因子相结合的交流机制的理解将增强人胚胎和诱导多能干细胞的生理细胞类型的分化。这将使神经胚胎学领域的新假设的制定和测试以及生物医学应用包括细胞治疗的神经细胞的优化生成成为可能。

The experiments outlined in this proposal will significantly enhance present knowledge of lineage specification and cell-cell interactions in human neural development. The development of the neural lineage (neuropoiesis) encompasses a number of highly fine-tuned stages and transitions. Major research efforts are aimed at the differentiation of pluripotent stem cells (PSCs) into biomedically relevant phenotypes. However, overall, our understanding of signaling pathways and regulatory networks underlying neural morphogenesis and phenotype specification has remained very limited. Current approaches of directed differentiation of PSCs result in inappropriate phenotypes and heterogenous, poorly controlled cultures, indicating that current in vitro protocols neglect the aspect of cell-cell interactions, and their relevance for appropriate patterning, positional specification and morphogenesis. To elucidate the nature of intercellular communication of such self-organized developmental systems, there is a need for investigating neural surface molecules and secreted factors as well as their respective interplay in the specification of neural phenotypes. We hypothesize that a mechanistic understanding of the communication between hPSC-derived neural cells via their respective differential cell surface signature in combination with secreted factors/diffusible morphogens will enhance the differentiation of physiological cell types from human embryonic and induced pluripotent stem cells, which will enable the formulation and testing of novel hypotheses in the fields of neuroembryology and optimized generation of neural cells for biomedical applications including cell therapy.