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育而来的，这些干细胞的任务是有组织地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但尚未解决的问题。大多数关于哺乳动物发育的研究都集中在确定指导组织形态发生的基因表达的变化上。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。这种额外的但难以捉摸的命运控制层允许细胞适应它们的动态环境。组织形状和细胞命运之间的联系在胚胎植入时尤为重要，胚胎在与子宫进行物理接触时经历了戏剧性的重组。这是哺乳动物发育的一个关键时期，与基因表达、细胞组织和整体胚胎模式和形态的变化有关，但由于胚胎的不可接近性，人们对其知之甚少。为了克服这一限制，最近建立了胚胎培养方法和3D干细胞模型，忠实地再现了植入时的发育。我们的目的是剖析细胞身份、细胞组织和组织形状的变化如何在小鼠和人类胚胎中协调一致，以确保身体计划的形成。利用最先进的转录组学、蛋白质组学、成像和体内功能实验，我们将确定多能干细胞在植入时进入上皮组织的组织如何影响它们的特性和随后分化成不同的细胞类型。利用我们独特的胚胎和干细胞培养，再现了植入时的形状-命运串扰，该项目独特地准备好了对正常胚胎发育的综合机制理解，这是确定发育失败，先天性异常和不孕症原因的第一步。

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.