Dissecting the interplay of gene regulatory networks and cellular niche on cell fate determination

一个全能受精卵具有产生整个多细胞有机体的非凡能力。 全面绘制和调整管理这一转型的参数的方法将具有 对我们对发育的理解以及我们恢复正常功能的能力产生了广泛的影响 受损的或有病的组织。虽然这些过程通常是在模型的背景下研究的 生物体，人类多能干细胞(HPSCs)的出现开启了一种强大的范式来 重述人类在体外环境中的发展。事实上，hPSC已经成功地分化为 大多数体细胞类型感兴趣，最近还转化为复杂的三维器官。这些 分化系统开始为人类生物学提供前所未有的洞察力，然而有两个 根本性的挑战依然存在：第一，使hPSC能够有效地分化为成熟的 与胚胎或胎儿组织起源类似的状态相比，重述成人的表型；以及第二， 可伸缩和架构可复制的器官类型组织的生成。重在辨肝论治 在本提案中，我们将从hPSC中探索这两个关键目标相互交织的假设，以及 获得成熟的表型可能与建立适当的细胞生态位有关。 为此，我们将开发一种集成的基因组工程和组织工程方法，将 允许在hPSC期间对遗传和细胞微环境参数进行系统操作 差异化。利用这个框架，我们希望能够更深入地理解基因之间的相互作用 调控网络和细胞生态位对细胞命运的决定；也可能指导 为再生医学应用规划器官发生过程的方法学。

A single totipotent zygote has the remarkable ability to give rise to an entire multi-cellular organism. Methodologies to comprehensively map and modulate the parameters that govern this transformation will have far ranging impact on our understanding of development and also our ability to restore normal function in damaged or diseased tissues. While these processes have typically been studied in the context of model organisms, the advent of human pluripotent stem cells (hPSCs) has opened a powerful paradigm to recapitulate human development in ex vivo settings. Indeed hPSCs have been successfully differentiated to most somatic cell types of interest and recently also into complex three-dimensional organoids. These differentiation systems are beginning to offer an unprecedented insight into human biology, however two fundamental challenges have persisted: one, enabling efficacious differentiation of hPSCs to a mature phenotype that recapitulates an adult versus an embryonic or fetal tissue-of-origin like state; and two, generation of scalable and architecturally reproducible organotypic tissues. Focusing on liver differentiation from hPSCs, in this proposal we will explore the hypothesis that these two key objectives are intertwined, and achieving a mature phenotype is potentially linked to the establishment of an appropriate cellular niche. Towards this we will develop an integrated genome engineering and tissue engineering approach that will allow systematic manipulation of both genetic and cellular microenvironmental parameters during hPSC differentiation. Using this framework we hope to enable a deeper understanding of the interplay of gene regulatory networks and cellular niche on cell fate determination; and also potentially guide development of methodologies towards programming the processes of organogenesis for regenerative medicine applications.