Mechanisms Governing Uterine Epithelial Plasticity

子宫上皮可塑性的调控机制

• 批准号: 10710938
• 负责人: Andrew M Kelleher
• 金额: $ 43.81万
• 依托单位: UNIVERSITY OF MISSOURI-COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-03 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10710938
• 关键词: 3-Dimensional; Ablation; Acute; Adult; Asherman Syndrome; Behavior; Biological; Biological Assay; Biology; Bone Marrow; Cell Differentiation process; Cell physiology; Cells; Childbirth; Chromatin; Chronic; Cicatrix; Complex; Data; Defect; Development; Diagnosis; Disease; Distant; Endometrial; Endometrial Carcinoma; Endometrium; Ensure; Epithelial Cells; Epithelium; Event; Fibroid Tumor; Genes; Genetic; Genetic Models; Genetic Transcription; Goals; Hematopoietic stem cells; Homeostasis; Human; Human body; Immune; In Vitro; Infertility; Injury; Knowledge; Location; Longevity; Menstruation; Messenger RNA; Molecular; Molecular Profiling; Mus; Natural regeneration; Organ; Organoids; Outcome; Pathway interactions; Pericytes; Periodicity; Phylogenetic Analysis; Physiological; Population; Pregnancy; Pregnancy Maintenance; Process; Proliferating; Regenerative Medicine; Regenerative capacity; Regenerative response; Reporter; Reporting; Research; Role; Stromal Cells; System; Technology; Testing; Tissue Engineering; Tissues; Uterus; Woman; cell regeneration; cell type; endometrial organoid; endometriosis; epithelial stem cell; epithelium regeneration; in vivo; injury and repair; innovation; mouse genetics; multiple omics; novel; population based; prevent; progenitor; recruit; regenerative; repaired; response; screening; single cell sequencing; stem; stem cell biology; stem cell model; stem cell population; stem cells; stem-like cell; success; therapeutic development; tissue regeneration; tissue repair; transcription factor

Project Summary/Abstract Unlike most other organs and tissues, the endometrium of the adult uterus has a remarkable regenerative ability, undergoing repetitive cycles of proliferation, differentiation, breakdown, and regeneration. The endometrium is a complex tissue comprised of stroma, vasculature and immune cells, as well as two major epithelial cell types — luminal (LE) and glandular (GE) epithelium. Notably, the endometrium repairs after menstruation, injury, and childbirth without scarring and then regenerates with full function to support pregnancy. Aberrations in regeneration negatively impacts pregnancy success and can lead to infertility or diseases, such as endometriosis, endometrial fibroids, Asherman’s syndrome, and endometrial cancer. Thus, the long-term research objective is to define the critical intrinsic and extrinsic mechanisms governing uterine epithelial cell differentiation and regeneration with subsequent impacts to diagnose, treat, and prevent infertility and endometrial disease in women. The regenerative capacity and ability to grow ectopically (endometriosis) suggests that the endometrium has a robust and plastic progenitor population. Indeed, numerous reports have provided evidence that cells with stem cell-like qualities exist in the epithelium of the uterus; however, the identity, behavior, and mechanisms underlying the fate of those cells and their location remains unclear. Ambiguity within the uterine stem cell field may be partly because the strict lineage hierarchies that characterize development and homeostatic tissue turnover are not followed during tissue repair. Recent studies in several organs found that epithelial plasticity and activation of facultative stem cells are common strategies for tissue regeneration in the injury repair process. Therefore, this proposal focuses more on the process used by the uterus to replace lost cells, rather than on the physical entity of a stem cell. The overarching hypothesis is that the uterine epithelium contains cells that are unipotent during normal homeostatic turnover but have the ability to dedifferentiate upon injury to coordinate successful epithelial regeneration. Guided by strong preliminary data and the use of innovative mouse genetic models, organoid culture, and single-cell sequencing technologies, two specific aims will begin testing that hypothesis: (1) epithelial plasticity in the regenerating uterus; and (2) cellular and molecular aspects of LE response to GE ablation. The outcome of the proposed studies will connect epithelial regeneration responses to specific molecular mechanisms of epithelial differentiation and repair. In the long term, an increased understanding of the cellular and molecular mechanisms that govern endometrial epithelial cell differentiation and regeneration is important not only for gaining fundamental knowledge of tissue and stem cell biology but also for the development of therapeutics for the treatment of endometrial diseases.

项目总结/摘要 与大多数其他器官和组织不同，成年子宫的子宫内膜具有显著的再生能力， 经历增殖、分化、分解和再生的重复循环。子宫内膜是 由基质、脉管系统和免疫细胞组成的复杂组织，以及两种主要的上皮细胞类型- 管腔（LE）和腺（GE）上皮。值得注意的是，子宫内膜在月经、损伤和 分娩时没有疤痕，然后再生，功能齐全，以支持怀孕。畸变 再生会对怀孕成功产生负面影响，并可能导致不孕或疾病，如 子宫内膜异位症、子宫内膜肌瘤、Asherman综合征和子宫内膜癌。因此，长期 研究目的是明确子宫上皮细胞的内在和外在调控机制， 分化和再生，以及随后对诊断、治疗和预防不孕症的影响， 女性子宫内膜疾病再生能力和异位生长能力（子宫内膜异位症） 提示子宫内膜有一个健壮的可塑性祖细胞群。事实上，许多报告 提供了具有干细胞样性质的细胞存在于子宫上皮中的证据;然而，这种特性， 行为，以及这些细胞的命运和它们的位置的机制仍然不清楚。内部的模糊性 子宫干细胞领域可能部分是因为严格的谱系等级， 在组织修复过程中不遵循稳态组织更新。最近对几个器官的研究发现， 上皮可塑性和兼性干细胞的活化是在哺乳动物中组织再生的常见策略。 损伤修复过程。因此，本建议更侧重于子宫用于替代丢失的过程 细胞，而不是干细胞的物理实体。总体假设是子宫上皮 包含在正常稳态周转期间是单能的细胞，但在正常稳态周转期间具有去分化的能力。 以协调成功的上皮再生。以强有力的初步数据为指导， 创新的小鼠遗传模型、类器官培养和单细胞测序技术， 将开始检验这一假设：（1）再生子宫上皮的可塑性;（2）细胞和分子的 LE对GE消融的反应方面。拟议研究的结果将连接上皮再生 对上皮分化和修复的特定分子机制的反应。从长远来看， 了解控制子宫内膜上皮细胞分化的细胞和分子机制 再生不仅对获得组织和干细胞生物学的基础知识很重要， 还用于开发治疗子宫内膜疾病的疗法。

项目成果

Estrogen receptor alpha regulates uterine epithelial lineage specification and homeostasis.

• DOI: 10.1016/j.isci.2023.107568
• 发表时间: 2023-09-15
• 期刊: ISCIENCE
• 影响因子: 5.8
• 作者: Rizo, Jason A.;Davenport, Kimberly M.;Winuthayanon, Wipawee;Spencer, Thomas E.;Kelleher, Andrew M.
• 通讯作者: Kelleher, Andrew M.