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.

项目概要 女性的子宫是一个独特的器官，能够在生育过程中经历反复的生理损伤和修复。 每月的月经周期。尤其是子宫内膜，在月经后会大量再生。 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 和修复，以及这些过程在调节不当时如何导致疾病/功能障碍，例如 子宫内膜癌、子宫内膜异位症、子宫内膜薄、阿什曼综合症和不孕症。在这个项目中， 实验旨在研究间充质-上皮转化（MET）作为一种机制 子宫内膜上皮再生。研究表明，MET 是子宫内膜发生变化的机制之一。 上皮细胞在产后和小鼠的月经样模型中再生，并被提议作为 女性的机制。在 MET（一种细胞转分化）过程中，间充质细胞 重新编程并转化为上皮细胞。据我们所知，子宫内膜是唯一能 在正常生理条件下使用细胞转分化（例如产后和月经样修复） 在成人中。不幸的是，我们对这种独特修复机制的理解非常不完整。两个具体 目的将进一步研究MET在上皮再生中的作用：（1）测试MET来源的子宫内膜的功能 上皮细胞； (2) 比较子宫内膜来源和骨髓 (BM) 来源间充质的 MET 细胞。小鼠模型的组合，包括谱系追踪、月经样子宫内膜破裂和修复 一种新的原位移植技术以及 scRNA-seq 将用于解决基本问题 有关 MET 衍生上皮细胞的功能、特征和起源的问题。特别是，无论他们 是真正的子宫内膜上皮细胞以及它们是否源自子宫内膜基质细胞和/或骨 骨髓细胞，将被研究。重要的是，原位移植将用于评估人类的 MET 基质细胞作为体内研究不能在女性中进行。适当的子宫内膜再生，包括 更换丢失或受损的上皮细胞，对于子宫的后续准备是必要的 生殖周期和怀孕。没有其他器官能像我们所看到的那样经历如此极端的组织再生 月经周期期间在子宫内。也许是由于子宫受损和修复的程度 经历了它会受到疾病发展的影响。加深对子宫内膜修复的了解 这些机制将提供更深入的了解，当这些过程出现问题时，如何促进子宫内膜 疾病并影响生育能力，最终带来更好的治疗方法。