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

项目总结 妇女的子宫是一个独特的器官，其能力是经历反复的生理损伤和修复 月经周期。尤其是子宫内膜，在月经后广泛再生。 正在脱落。我们的长期研究目标是了解子宫内膜再生的正常机制 以及当这些过程被错误调控时，如何导致疾病/功能障碍，如 子宫内膜癌、子宫内膜异位症、子宫内膜变薄、阿舍曼综合征和不孕症。在这个项目中， 实验旨在研究间充质-上皮转化(MET)作为一种 子宫内膜上皮再生。研究表明MET是子宫内膜的一种机制 在小鼠中，上皮在产后和月经样模型中再生，已被认为是一种 女性的生理机制。在MET期间，这是一种细胞转分化，间充质细胞是 重新编程并转化为上皮细胞。据我们所知，子宫内膜是唯一一种 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) 在成人身上。不幸的是，我们对这种独特的修复机制的了解非常不完整。两个具体的 AIMS将进一步研究MET在上皮再生中的作用：(1)检测MET来源的子宫内膜的功能 (2)比较子宫内膜来源的间充质细胞和骨髓来源的间充质细胞。 细胞。包括血统追踪、月经样子宫内膜破裂和修复在内的小鼠模型的组合 一种新的原位移植技术和scrna-seq将被用于解决基本的 关于甲硫氨酸来源的上皮细胞的功能、特征和来源的问题。尤其是，他们是否 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 骨髓细胞，将被研究。重要的是，原位移植将被用来评估人类MET 间质细胞在体内的研究不能在女性身上进行。正确的子宫内膜再生，包括 替换丢失或受损的上皮细胞，是为后续子宫做准备所必需的 生殖周期和怀孕。没有其他器官会像我们看到的那样受到如此极端的组织再生的影响 在月经周期的子宫里。可能是因为损伤和修复的程度，子宫 它会受到疾病发展的影响。增加对子宫内膜修复的了解 这些机制将提供更深入的了解，当这些过程出错时，如何促进子宫内膜 疾病和影响生育最终导致更好的治疗方法。

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.