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.

项目摘要/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， 重复的经历增殖、分化、分解和再生的重复循环的子宫内膜是一种 由基质、血管系统和免疫细胞以及两种主要的上皮细胞类型组成的复杂组织- 腔(LE)和腺(GE)上皮。值得注意的是，子宫内膜在月经、损伤和 分娩时不会留下疤痕，然后再生，具有支持怀孕的全部功能。中的像差 再生对妊娠成功有负面影响，并可能导致不孕或疾病，例如 子宫内膜异位症、子宫内膜纤维瘤、阿舍曼综合征和子宫内膜癌。因此，从长远来看， 研究目的是明确子宫上皮细胞的关键内在和外在机制。 分化和再生，对诊断、治疗和预防不孕不育和 女性的子宫内膜病。再生能力和异位生长能力(子宫内膜异位症) 这表明子宫内膜具有强大的可塑性前体细胞群。事实上，许多报告都有 提供证据表明子宫上皮中存在具有干细胞样性质的细胞；然而，身份， 这些细胞的行为、潜在的命运和它们的位置仍然不清楚。内在的歧义 子宫干细胞领域可能部分是因为严格的谱系等级，这是发育和 在组织修复过程中不遵循动态平衡的组织周转。最近对几个器官的研究发现 上皮的可塑性和兼性干细胞的激活是组织再生的常见策略 损伤修复过程。因此，这项建议更侧重于子宫用来替代丢失的过程 细胞，而不是干细胞的物理实体。最重要的假设是子宫上皮 包含在正常内环境平衡周转期间具有单能性的细胞，但具有在 损伤以协调成功的上皮再生。以强劲的初步数据为指导，使用 创新的小鼠遗传模型、器官培养和单细胞测序技术，这是两个特别的目标 将开始检验这一假设：(1)再生子宫中的上皮可塑性；以及(2)细胞和分子 LE对Ge消融反应的一些方面。拟议的研究结果将把上皮再生联系起来 对上皮分化和修复的特定分子机制的反应。从长远来看，增加 了解调控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，而且 也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.