Impact of tissue morphology on pluripotent stem cell identity and fate

哺乳动物是从一小群多能干细胞发展而来的，这些干细胞的任务是以有组织的方式产生生物体的所有细胞类型和组织形状。它们是如何做到这一点的，这是生物学中一个重要而尚未解决的问题。大多数关于哺乳动物发育的研究都集中在识别引导组织形态发生的基因表达的变化。然而，最近的证据表明，组织形状的变化会影响基因调控网络，从而影响细胞的命运。这种额外而又难以捉摸的命运控制层使细胞能够适应动态环境。组织形状和细胞命运之间的联系在着床时尤其相关，当胚胎与子宫接触时，胚胎经历了戏剧性的重组。这是哺乳动物发育的关键时期，与基因表达、细胞组织以及整体胚胎外观和形态的变化有关，但由于胚胎的不可获得性，人们对此知之甚少。为了克服这一局限性，最近建立了胚胎培养方法和3D干细胞模型，真实地概括了植入时的发育情况。我们的目的是剖析在小鼠和人类胚胎中，细胞特性、细胞组织和组织形状的变化是如何协调的，以确保体型计划的形成。利用最先进的转录组学、蛋白质组学、成像和活体实验中的功能，我们将确定在植入时将多能干细胞组织成上皮组织如何影响它们的实体以及随后指定为不同细胞类型。利用我们独特的胚胎和干细胞培养，概括了植入时形状和命运的串扰，该项目独一无二地准备好产生一个完整的机制，以了解正常胚胎发育，这是确定发育失败、先天性异常和不孕不育原因的第一个基本步骤。

Mammals develop from a small group of pluripotent stem cells that have the task to generate all the cell types and tissue shapes ofthe organism in an organised manner. How they achieve this is an important and unsolved problem in biology. Most studies ofmammalian development have focused on identifying changes in gene expression that guide tissue morphogenesis. However, recentevidence indicates that changes in tissue shape impinge on gene regulatory networks to affect cell fate. This additional yet elusivelayer of fate control allows cells to adapt to their dynamic environment. The link between tissue shape and cell fate is particularlyrelevant at implantation, when the embryo undergoes a dramatic reorganisation as it comes into physical contact with the uterus.This is a critical period in mammalian development associated with changes in gene expression, cell organisation, and overall embryopatterning and morphology, but is poorly understood due to the inaccessibility of the embryo. To overcome this limitation, werecently established embryo culture methods and 3D stem cell models that faithfully recapitulate development at implantation. Weaim to dissect how changes in cell identity, cell organisation, and tissue shape are coordinated in mouse and human embryos toensure the formation of the body plan. Employing state-of-the-art transcriptomics, proteomics, imaging and functional in vivoexperiments, we will determine how the organisation of pluripotent stem cells into an epithelial tissue at implantation affects theiridentity and subsequent specification into distinct cell types. Capitalising on our unique embryo and stem cell cultures thatrecapitulate the shape-fate crosstalk at implantation, this project is uniquely well-poised to yield an integrated mechanisticunderstanding of normal embryo development, a first fundamental step in identifying the causes of developmental failure,congenital abnormalities and infertility.