Functional characterization of mesenchymal-epithelial transition (MET)-derived cells in normal endometrial regeneration

正常子宫内膜再生中间充质-上皮转化（MET）衍生细胞的功能特征

• 批准号: 10404685
• 负责人: Amanda Patterson
• 金额: $ 32.6万
• 依托单位: UNIVERSITY OF MISSOURI-COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-15 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10404685
• 关键词: Address; Adult; Asherman Syndrome; Bone Marrow; Bone Marrow Cells; Cell physiology; Cells; Characteristics; Development; Disease; Embryo; Embryonic Development; Endometrial; Endometrial Carcinoma; Endometrial Stromal Cell; Endometrium; Epithelial; Epithelial Cells; Female infertility; Fertility; Functional disorder; Goals; Hormone Responsive; Human; In Vitro; Infertility; Investigation; Knowledge; Label; Malignant Neoplasms; Menstrual cycle; Menstruation; Mesenchymal; Modeling; Mus; Natural regeneration; Organ; Pathway interactions; Physiological; Postpartum Period; Pregnancy; Preparation; Process; Regulation; Reporter; Reporting; Research; Role; Stromal Cells; Structure of paramesonephric duct; Techniques; Testing; Therapeutic; Thinness; Tissues; Transitional Epithelium; Transplantation; Uterine Diseases; Uterus; Woman; Work; base; cell type; design; endometriosis; epithelial repair; epithelium regeneration; experimental study; in vivo; innovation; insight; mouse model; natural Blastocyst Implantation; novel; repaired; reproductive; single-cell RNA sequencing; stem; stem cells; theories; tissue regeneration; transcriptome; transdifferentiation; transplant model

PROJECT SUMMARY The uterus in women is a unique organ in its ability to undergo repeated physiological damage and repair during the monthly menstrual cycle. The endometrium, in particular, is extensively regenerated following menstrual shedding. Our long-term research goal is to understand the normal mechanisms of endometrial regeneration and repair and how these processes, when mis-regulated, contribute to diseases/dysfunction such as endometrial cancer, endometriosis, thin endometrium, Asherman’s Syndrome and infertility. In this project, experiments are designed to investigate mesenchymal-epithelial transition (MET) as a mechanism of endometrial epithelial regeneration. Research shows that MET is one mechanism by which the endometrial epithelium is regenerated postpartum and in a menses-like model in mice and has been proposed as a mechanism in women. During MET, which is a type of cellular transdifferentiation, a mesenchymal cell is reprogrammed and converted into an epithelial cell. To our knowledge, the endometrium is the only tissue that uses cellular transdifferentiation under normal physiological conditions (e.g. postpartum and menses-like repair) in the adult. Unfortunately, our understanding of this unique repair mechanism is very incomplete. Two specific aims will further investigate MET in epithelial regeneration: (1) Test the function of MET-derived endometrial epithelial cells; and (2) Compare MET by endometrial-derived and bone marrow (BM)-derived mesenchymal cells. A combination of mouse models including lineage tracing, menses-like endometrial breakdown and repair and a novel orthotopic transplantation technique along with scRNA-seq will be employed to address fundamental questions about the function, characteristics, and origin of MET-derived epithelial cells. Particularly, whether they are bona fide endometrial epithelial cells and whether they originate from endometrial stromal cells and/or bone marrow cells, will be investigated. Importantly, orthotopic transplantation will be used to assess MET by human stromal cells as in vivo studies cannot be performed in women. Proper endometrial regeneration, including replacement of lost or damaged epithelial cells, is necessary for preparation of the uterus for subsequent reproductive cycles and pregnancy. No other organ is subject to such extreme tissue regeneration as that seen in the uterus during the menstrual cycle. It is perhaps because of the extent of damage and repair that the uterus undergoes that it is subject to development of diseases. Increased understanding of endometrial repair mechanisms will provide greater insight into how these processes, when gone awry, contribute to endometrial diseases and impact fertility ultimately leading to better therapeutics.

项目摘要 女性的子宫是一个独特的器官 月经周期。特别是子宫内膜在月经后广泛再生 脱落。我们的长期研究目标是了解子宫内膜再生的正常机制 维修以及这些过程在错误调节时如何导致疾病/功能障碍，例如 子宫内膜癌，子宫内膜异位症，子宫内膜薄，阿什曼综合征和不育症。在这个项目中， 实验旨在研究间质上皮转变（MET）作为一种机制 子宫内膜上皮再生。研究表明，MET是子宫内膜的一种机制 上皮是产后再生的，在小鼠的月经样模型中，已被提议作为一种 女性机制。在Met期间，这是一种细胞转分解的类型，间充质细胞为 重新编程并转换为上皮细胞。据我们所知，子宫内膜是唯一的组织 在正常的生理条件下使用细胞转分解（例如产后和月经样修复） 在成年人中。不幸的是，我们对这种独特的维修机制的理解非常不完整。两个具体 目标将进一步调查上皮再生：（1）测试MET衍生的子宫内镜的功能 上皮细胞； （2）比较子宫内膜衍生的骨髓（BM）衍生的间充质 细胞。小鼠模型的组合，包括谱系跟踪，类似月经的子宫内膜崩溃和修复 并将采用一种新型的原位移植技术以及SCRNA-Seq来解决基本 有关Met衍生上皮细胞的功能，特征和起源的问题。特别是他们 是真正的子宫内膜上皮细胞以及它们是否起源于子宫内膜基质细胞和/或骨骼 将研究骨髓细胞。重要的是，原位移植将用于评估人类的满足 在女性中不能进行体内研究的基质细胞。适当的子宫内膜再生，包括 替换丢失或受损的上皮细胞是准备子宫所必需的 生殖周期和怀孕。没有其他器官受到极端组织再生的约束 在月经周期中的子宫中。子宫可能由于损害和修复程度 经历它会受到疾病的发展。对子宫内膜修复的了解增加 机制将提供更深入的洞察力，了解这些过程在出现问题时如何有助于内部测定法 疾病和影响生育能力最终导致更好的治疗剂。