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

• 批准号: 10356919
• 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
• 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/10356919
• 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; Epithelial Cell Proliferation; Epithelial Cells; Exhibits; Experimental Models; Exposure to; Extracellular Matrix; Failure; Fetal Membranes; Fetus; Fissural; Functional disorder; Generations; Homeostasis; Impairment; In Situ; In Vitro; Infection; Inflammation; Inflammatory; Intervention; Investigation; Kinetics; Knowledge; Label; Laboratories; Lead; Magnetism; Mechanics; Membrane; Mesenchymal; Methodology; Methods; Microfluidics; Microscopy; Modeling; Molecular; Monitor; Oxidative Stress; Pathologic; Pathway interactions; Physiological Processes; Pregnancy; Pregnancy Complications; Premature Birth; Process; Property; Proteins; Recycling; Research; Risk; Role; Signal Transduction; Site; System; Technology; Testing; Time; Tissues; Transitional Epithelium; 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; multidisciplinary; organ on a chip; premature; preterm premature rupture of membranes; prototype; repaired; response; risk minimization; seal; second harmonic; senescence

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（羊膜变量）在怀孕期间保护胎儿。术语，感应（衰老）和炎症会导致膜细胞的功能和机械不稳定性，从而导致分娩。过早的感应和膜功能障碍与早产（PTB）和膜早产相关（PPROM）。然而，在妊娠期间导致膜稳定性的细胞水平变化及其功能障碍导致劳动和分娩尚不清楚。最新对感觉学期和早产膜的研究表明，“微裂缝”（MFS），细胞重塑的位点。在妊娠期间，将MFS重新分配以保持膜完整性。与相对对照相比，较高的MF数量及其在术语，PPROM和PTB膜上的形态计量学（深度和宽度）的增加表明MFS的重新密封受到损害。已经观察到经过上皮间质转变（EMT）的MF中的羊膜上皮细胞。此外，这些细胞显示出深层化（无裸细胞）区域的增殖和重新密封特性，以稳定膜。在MFS的愈合边缘，羊膜间充质细胞暴露了反向现象，间质上皮过渡（MET）。从这些发现中，我们假设细胞过渡对于维持胎儿膜完整性至关重要。我们 假设MFS是膜重塑的区域，其数量和形态计量学的增加与未能重塑和功能障碍膜有关。了解细胞间和细胞矩阵 导致MFS发育及其重新密封的相互作用将有助于我们确定氧化压力（OS）如何 炎症可能有助于PTB和PPROM中MFS和功能失调的膜状态的持久性。要测试的两个具体目的是特定的目标1：与正常情况相比，在OS和感染 /感染期间，在OS和感染 /感染过程中，胎膜上皮的动态重塑与无细胞（裸）膜的体外模型进行了动态重塑；特定目的2：确定使用胎儿膜器官芯片方法的细胞迁移，基质降解和与MFS形成相关的细胞转变。该多学科建议结合了细胞和分子生物学和生物工程学方法，旨在通过使用芯片上的器官芯片技术开发胎儿膜，以克服经典2D细胞培养物的局限性。该模型系统将与恒定的动态相互作用保持多种细胞类型，类似于子宫内的条件。我们将阐明（正常和异常）生物学MFS的形成以及它们如何对PTB和PPROM的贡献。了解细胞水平的机制将使我们能够设计策略，以最大程度地减少MFS的发育，以增强宫内腔内的空腔并降低PTB和PPROM的风险。