Impact of tissue morphology on pluripotent stem cell identity and fate

组织形态对多能干细胞身份和命运的影响

• 批准号: EP/X023044/1
• 负责人: Marta Shahbazi Alonso
• 金额: $ 154.11万
• 依托单位: MRC Laboratory of Molecular Biology
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=EP%2FX023044%2F1
• 关键词: Impact; tissue; morphology; pluripotent; stem

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.

哺乳动物是由一小群多能干细胞发育而来的，它们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。它们如何实现这一点是生物学中一个重要而未解决的问题。大多数关于哺乳动物发育的研究都集中在识别指导组织形态发生的基因表达变化上。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。这一额外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植入时尤为重要，当胚胎与子宫发生物理接触时，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，细胞组织和整体胚胎图案和形态的变化有关，但由于胚胎的不可接近性而知之甚少。为了克服这一限制，我们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。Weaim将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，以确保身体计划的形成。采用最先进的转录组学，蛋白质组学，成像和功能在体内实验中，我们将确定如何组织的多能干细胞植入上皮组织影响他们的身份和随后的规格成不同的细胞类型。利用我们独特的胚胎和干细胞培养，重现了植入时的形状-命运串扰，该项目非常适合于对正常胚胎发育进行综合的机械理解，这是确定发育失败，先天性异常和不育原因的第一个基本步骤。