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.

项目概要： 间充质-上皮转化（MET）在许多组织成形中起着重要作用。 包括胚胎发育，纤维化和干细胞重编程，但我们对这些过程知之甚少。 启动和调节MET的生物力学线索，MET调节哪些途径，以及新的 上皮化的簇的尺寸增大。在这个项目中，我们试图定义生物物理和生物力学 在心脏早期发育期间体内和3D间充质内离体指导MET的原理 集料.在心脏发育过程中，体内MET作为心脏祖细胞的双侧群体发生 向腹侧中线迁移我们已经开发了一个实验模型系统，其中METs的形状 非洲爪蟾早期心脏原基和另一个离体3D中MET自发发生的地方 X的聚集体。胚胎间充质细胞这些模型与活体显微镜兼容， 独特地可用于组合的生物物理、生物力学、细胞生物学和遗传分析。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之间复杂的相互作用， 体内和离体MET。心脏前体细胞的活体成像显示，它们改变了它们的 机械迁移模式，因为他们经历MET。我们的实验室还发现，两种模型中的MET 对组织张力和细胞收缩性高度敏感。在我们的第一个目标中，我们专注于描述表型 心脏祖细胞在接受MET时的变化以及MET如何改变其力学和迁移 通过细胞密集的微环境。我们的第二个目标是确定机械和分子途径 在3D间充质聚集体中驱动MET，专注于在这个过程中抑制机械线索的途径， 过程在我们的第三个目标中，我们探索了MET在3D聚集体中的起始和扩散的细胞生物学，并测试了MET在3D聚集体中的表达。 我们在心脏形成的3D离体模型中的发现。我们的研究集中在体内和体外模型 的MET，以确定和测试心脏形成过程中MET中的机械线索的作用，以及生物力学 并且生物物理过程与驱动组织组装的细胞生物过程整合。由于 发展中的MET与其他系统中的MET的相似性，我们的研究结果可能会揭示共同的 在再生、伤口愈合、纤维化和癌症转移过程中调节MET的途径。