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

项目摘要 女性的子宫是一个独特的器官，它有能力在怀孕期间经历反复的生理损伤和修复。 每月的月经周期。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 以及这些过程在受到错误调节时如何导致疾病/功能障碍， 子宫内膜癌、子宫内膜异位症、薄子宫内膜、Asherman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）作为一种机制， 子宫内膜上皮再生研究表明MET是子宫内膜 上皮在产后和小鼠月经样模型中再生， 女人的机制。在MET（其是一种细胞转分化）期间，间充质细胞被转化为细胞。 重新编程并转化为上皮细胞。据我们所知，子宫内膜是唯一的组织， 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，我们对这种独特的修复机制的理解非常不完整。两个具体 本研究旨在进一步探讨MET在上皮再生中的作用：（1）检测MET源性子宫内膜的功能 上皮细胞;和（2）通过尿道衍生的和骨髓（BM）衍生的间充质细胞比较MET 细胞包括谱系追踪、月经样子宫内膜破裂和修复的小鼠模型的组合 一种新的原位移植技术沿着scRNA-seq将被用来解决基本的 关于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，以及它们是否来源于子宫内膜基质细胞和/或骨 骨髓细胞，将进行研究。重要的是，原位移植将用于评估人MET 基质细胞作为体内研究不能在妇女中进行。子宫内膜再生，包括 更换丢失或受损的上皮细胞，对于准备子宫进行随后的手术是必要的。 生殖周期和怀孕。没有其他器官像我们看到的那样， 在月经周期的子宫里。这可能是因为损伤和修复的程度， 经历了它是受疾病的发展。增加对子宫内膜修复的了解 机制将提供更深入的了解这些过程，当出错时，如何有助于子宫内膜 疾病和影响生育能力，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.