Mechanical Control of Mesenchymal-to-Epithelial Transition

间充质到上皮转变的机械控制

• 批准号: 9336427
• 负责人: LANCE A. DAVIDSON
• 金额: $ 54.96万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-15 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9336427
• 关键词: Apical; Behavior; Bilateral; Biological; Biological Models; Biological Process; Biomechanics; Biophysical Process; Cell Adhesion; Cells; Cellular Structures; Cellular biology; Cereals; Chemicals; Complex; Cues; Data; Development; Diagnostic tests; Disease; Embryo; Embryonic Development; Environment; Epithelial; Epithelium; Event; Experimental Models; Fibrosis; Gene Expression; Genes; Genomics; Goals; Heart; Hour; In Vitro; Life; Location; Malignant Neoplasms; Maps; Mechanical Stress; Mechanics; Mesenchymal; Microscopic; Microscopy; Modeling; Molecular; Monitor; Movement; Natural regeneration; Neoplasm Metastasis; Organ; Organogenesis; Pathway Analysis; Pathway interactions; Phenotype; Play; Population; Process; Proteins; Rana; Regulation; Research; Research Personnel; Role; Shapes; Stem cells; Study models; Surface; System; Testing; Therapeutic; Tissues; Traction; Universities; Wound Healing; Xenopus laevis; base; biophysical techniques; cardiogenesis; cell motility; cell type; embryo cell; epithelial to mesenchymal transition; genetic analysis; heart primordium; in vivo; in vivo Model; insight; intravital imaging; migration; precursor cell; progenitor; programs; self assembly; success; temporal measurement; three-dimensional modeling; tool; transcriptome

Project Summary: Mesenchymal-to-epithelial transitions (METs) play fundamental roles in many tissue-shaping processes including embryonic development, fibrosis, and stem cell reprogramming, yet we know little about the biomechanical cues that initiate and regulate METs, what pathways are regulated by METs, and how newly epithelialized clusters grow in size. In this project we seek to define the biophysical and biomechanical principles that guide MET in vivo during early development of the heart and ex vivo within 3D mesenchymal aggregates. During heart development, in vivo METs occur as bilateral populations of heart progenitor cells migrate toward the ventral midline. We have developed one experimental model system in which METs shape the early heart primordia in Xenopus laevis and another where METs occur spontaneously in ex vivo 3D aggregates of X. laevis embryonic mesenchymal cells. These models are compatible with live microscopy and are uniquely accessible to combined biophysical, biomechanical, cell biological, and genetic analysis. Using these models, studies in our lab have revealed a complex interplay between cell and tissue biomechanics and MET both in vivo and ex vivo. Intra vital imaging of heart precursor cells reveals that they change their mechanical mode of migration as they undergo MET. Our lab has also found that METs in both models are highly sensitive to tissue tension and cell contractility. In our first aim we focus on describing phenotypic changes in heart progenitor cells as they undergo MET and how MET alters their mechanics and migration through a cell dense microenvironment. Our second aim seeks to identify mechanical and molecular pathways that drive MET in 3D mesenchymal aggregates, focusing on pathways that transduce mechanical cues in this process. In our third aim, we explore the cell biology of MET initiation and spreading in 3D aggregates and test our findings within a 3D ex vivo model of heart formation. We focus our studies on in vivo and ex vivo models of MET to identify and test the role of mechanical cues in MET during heart formation and how biomechanical and biophysical processes integrate with the cell biological processes that drive tissue assembly. Due to the similarities of developmental METs with METs in other systems, our findings will likely expose common pathways regulating METs during regeneration, wound healing, fibrosis, and cancers metastases.

项目总结： 间充质-上皮间充质转化(METS)在许多组织塑造中起着基础性作用 包括胚胎发育、纤维化和干细胞重编程等过程，但我们对此知之甚少 启动和调节蛋氨酸的生物力学线索，甲硫氨酸调节的途径是什么，以及新的 上皮化团的大小逐渐增大。在这个项目中，我们试图定义生物物理和生物力学 指导心脏早期发育的体内和体外3D间充质内MET的原则 集合体。在心脏发育过程中，体内的蛋氨酸以双侧心脏前体细胞群的形式出现 向腹中线移动。我们开发了一个实验模型系统，在这个系统中，Mets形成了 非洲爪哇和另一种甲硫氨酸在体外3D中自发发生的早期心脏原基 莱氏X.laevis胚胎间充质细胞聚集体。这些模型与活显微镜兼容，并且 是唯一可用于生物物理、生物力学、细胞生物学和遗传分析的组合。vbl.使用 这些模型，我们实验室的研究揭示了细胞和组织生物力学和 在体内和体外都相遇。心脏前体细胞的活体成像显示，它们改变了它们的 它们在经历相遇时的机械迁移方式。我们的实验室还发现，两种模型中的Met都是 对组织张力和细胞收缩高度敏感。在我们的第一个目标中，我们专注于描述表型 心脏祖细胞在经历MET时的变化以及MET如何改变其机制和迁移 通过细胞密集的微环境。我们的第二个目标是找出机械和分子途径 这种驱动力在3D间充质聚集体中相遇，专注于在这一过程中传递机械线索的途径 进程。在我们的第三个目标中，我们探索了MET在3D聚集体中的启动和扩散的细胞生物学并进行了测试 我们在心脏形成的3D体外模型中的发现。我们专注于体内和体外模型的研究。 在心脏形成过程中识别和测试机械信号在MET中的作用以及生物力学如何 生物物理过程与驱动组织组装的细胞生物过程相结合。由于 发育中的蛋氨酸与其他系统中的蛋氨酸的相似性，我们的发现可能会揭示共同的 在再生、伤口愈合、纤维化和癌症转移过程中调节蛋氨酸的途径。