Mechanical Control of Mesenchymal-to-Epithelial Transition

间充质到上皮转变的机械控制

基本信息

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
项目类别：
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

项目摘要

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：间充质到上皮的转变（MET）在许多组织塑造中发挥着重要作用包括胚胎发育、纤维化和干细胞重编程在内的过程，但我们对此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近如何调节上皮化簇变大。在这个项目中，我们试图定义生物物理和生物力学心脏早期发育过程中体内和 3D 间充质体外体内指导 MET 的原则聚合体。在心脏发育过程中，体内 MET 以双侧心脏祖细胞群的形式出现向腹中线迁移。我们开发了一种实验模型系统，其中 MET 形成非洲爪蟾的早期心脏原基和另一种在体外 3D 中自发发生 MET 的心脏原基 X. laevis 胚胎间充质细胞的聚集体。这些型号与实时显微镜兼容可以独特地进行生物物理、生物力学、细胞生物学和遗传分析的组合。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 MET 体内和离体。心脏前体细胞的生命体内成像显示它们改变了它们的当它们经历 MET 时的机械迁移模式。我们的实验室还发现这两个模型中的 MET 都是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 时发生的变化以及 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驱动 3D 间充质聚集体中的 MET，重点关注在此过程中转导机械线索的途径过程。我们的第三个目标是探索 MET 在 3D 聚集体中启动和扩散的细胞生物学并进行测试我们在心脏形成的 3D 离体模型中的发现。我们的研究重点是体内和离体模型 MET 来识别和测试心脏形成过程中 MET 中机械线索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 MET 与其他系统中的 MET 存在相似之处，我们的研究结果可能会揭示共同点再生、伤口愈合、纤维化和癌症转移过程中调节 MET 的途径。