Intercellular interactions define cell migrations and transitions that maintain fetal membrane homeostasis

细胞间相互作用定义了维持胎膜稳态的细胞迁移和转变

基本信息

批准号：
10571858
负责人：
Arum Han
金额：
$ 43.99万
依托单位：
UNIVERSITY OF TEXAS MED BR GALVESTON
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-03-12 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10571858
关键词：
Aging Amniotic Fluid Area Basement membrane Biological Biological Assay Biological Models Biomedical Engineering Birth Cell Communication Cell Culture Techniques Cell Shape Cell membrane Cell model Cell physiology Cells Characteristics Development Devices Environment Epithelial Cell Proliferation Epithelial Cells Epithelium Exhibits Experimental Models Exposure to Extracellular Matrix Failure Fetal Membranes Fetus Functional disorder Generations Green Fluorescent Proteins Homeostasis Impairment In Situ In Vitro Infection Inflammation Inflammatory Intervention Investigation Kinetics Knowledge Label Laboratories Magnetism Mechanics Membrane Mesenchymal Methodology Methods Microfluidics Microscopy Modeling Molecular Monitor Oxidative Stress Pathologic Pathway interactions Physiological Processes Pregnancy Pregnancy Complications Premature Birth Premature Rupture Fetal Membranes Process Property Recycling Research Risk Reduction Role Signal Transduction Site System Technology Testing Tissues Transfection Translating Urea Uterine cavity Width amnion bone fracture repair cell motility cell type design epithelial to mesenchymal transition fetus cell healing improved in utero in vitro Model innovation membrane model migration morphometry multi-photon multidisciplinary organ on a chip premature preterm premature rupture of membranes prototype repaired response risk minimization seal second harmonic senescence

项目摘要

Fetal membranes (amniochorion) protect the fetus during pregnancy. At term, senescence (aging) and inflammation cause functional and mechanical instability to membrane cells, contributing to parturition. Premature senescence and membrane dysfunctions are associated with preterm birth (PTB) and preterm premature rupture of the membranes (pPROM). However, cellular-level changes contributing to membrane stability during gestation and its dysfunction leading to labor and delivery are still unclear. Recent studies of senescent term and preterm membranes revealed “microfractures” (MFs), sites of cellular remodeling. MFs are resealed during gestation to maintain membrane integrity. Higher numbers of MFs and their increased morphometry (depth and width) in term labor, pPROM, and PTB membranes compared to respective controls suggest MFs' resealing is compromised. Amnion epithelial cells in MFs have been observed undergoing epithelial mesenchymal transition (EMT). Further, these cells showed proliferative and resealing properties of deepithelialized (nude/cell free) areas to stabilize membranes. At the healing edge of MFs, amnion mesenchymal cells exhibited a reverse phenomenon, mesenchymal-epithelial transition (MET). From these findings, we postulate that cellular transitions are essential for maintaining fetal membrane integrity. We hypothesize that MFs are areas of membrane remodeling and their increased number and morphometry are associated with failure to remodel and dysfunctional membranes. Understanding intercellular and cell-matrix interactions causing MFs' development and their resealing will help us to determine how oxidative stress (OS) and inflammation can contribute to the persistence of MFs and dysfunctional membrane status in PTB and pPROM. Two specific aims to be tested are Specific Aim 1: To investigate the dynamic remodeling of the fetal membrane epithelium in an in vitro model of cell-free (nude) membranes during OS and infection / inflammation compared to normal conditions; Specific Aim 2: To determine cell migration, matrix degradation, and cellular transition associated with MFs' formation using a fetal membrane organ-on-a-chip approach. This multidisciplinary proposal combines cell and molecular biological and bioengineering approaches designed to overcome the limitations of classic 2D cell cultures by developing a fetal membrane-on-a-chip using organ-on-chip technologies. This model system will maintain multiple cell types in close proximity with constant dynamic interactions, similar to the conditions in utero. We will elucidate causative molecular mechanisms of (normal and abnormal) biologic MFs' formation and how they contribute to PTB and pPROM. Understanding cellular-level mechanisms will allow us to design strategies to minimize MFs' development to strengthen intrauterine cavities and reduce the risk of PTB and pPROM.

胎儿膜（羊膜）在怀孕期间保护胎儿，衰老（老化）和炎症会导致膜细胞的功能和机械不稳定，从而导致早产（PTB）和早产。然而，导致妊娠期间膜稳定性的细胞水平变化及其导致临产和分娩的功能障碍的最新研究仍不清楚。与相应的足月产膜相比，早产膜出现“微裂纹”（MF），细胞重塑部位在妊娠期间重新封闭，以保持膜的完整性。对照表明，MF 中的羊膜上皮细胞发生上皮间质转化 (EMT)。这些细胞表现出去上皮（裸露/无细胞）区域的增殖和重新封闭特性，以稳定 MF 的愈合边缘，羊膜间充质细胞表现出相反的现象，即间充质-上皮转化 (MET)。细胞转变对于维持胎膜完整性至关重要。 MF 是膜重塑的区域，其数量和形态测量的增加与膜重塑失败和功能失调有关。导致 MF 发展及其重新封闭的相互作用将帮助我们确定氧化应激 (OS) 炎症可能导致 PTB 和 pPROM 中 MF 的持续存在和功能失调的膜状态。具体目标 1：研究体外无细胞（裸）模型中胎儿膜上皮的动态重塑。 ) 与正常条件相比，OS 和感染/炎症期间的膜；具体目标 2：使用胎儿膜器官芯片方法确定与 MF 形成相关的细胞迁移、基质降解和细胞转变。多学科提案结合了细胞和分子生物学以及生物工程方法，旨在通过使用芯片上器官技术开发胎儿膜芯片来克服经典二维细胞培养的局限性。该模型系统将保持多种细胞类型紧密相连。与子宫内条件类似，我们将阐明（正常和异常）生物 MF 形成的致病分子机制以及它们如何促进 PTB 和 pPROM。了解细胞水平机制将使我们能够设计策略。最大限度地减少 MF 的发育，强化宫腔并降低 PTB 和 pPROM 的风险。