Functional Analysis of Endometrial Stem/Progenitor Cells

子宫内膜干/祖细胞的功能分析

• 批准号: 7978454
• 负责人: James K Pru
• 金额: $ 21.41万
• 依托单位: WASHINGTON STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7978454
• 关键词: A Mouse; Adult; Affect; Architecture; Area; Birth; Blood Cells; Bone Marrow; Bone Marrow Transplantation; Cell physiology; Cells; Cellular biology; Cervix Uteri; Conceptions; Decidual Cell Reactions; Development; Developmental Process; Diagnosis; Differentiation and Growth; Endometrial; Endometrial Carcinoma; Endometrial Cycles; Endometrium; Epithelial; Epithelium; Estrous Cycle; Etiology; Event; Exhibits; Female; Fertility; Fibroblasts; Functional disorder; Goals; Growth; Gynecologic Pathology; Human; Implant; Infertility; Infusion procedures; Label; Link; Maintenance; Mammalian Oviducts; Mammals; Maps; Menstrual cycle; Menstruation; Morbidity - disease rate; Myometrial; Natural regeneration; Organ; Ovarian; Ovary; Parabiosis; Pathology; Pelvic Pain; Physiologic pulse; Physiology; Plastics; Play; Pregnancy; Pregnancy Maintenance; Pregnancy loss; Preparation; Process; Quality of life; Recruitment Activity; Recurrence; Reproduction; Residual state; Rodent; Role; Spontaneous abortion; Stem Cell Research; Stem cells; Stromal Cells; Testing; Therapeutic Intervention; Tissues; Transgenic Mice; Transplantation; United States; Uterine Diseases; Uterus; Vagina; Woman; adult stem cell; aged; body system; endometriosis; human female; in vivo; male; migration; mortality; mouse model; nonhuman primate; postnatal; programs; public health relevance; regenerative; repaired; reproductive; research study; stem; stem cell biology; steroid hormone; tissue regeneration

DESCRIPTION (provided by applicant): Uterine disease is an extremely common factor affecting the quality of life and morbidity/mortality of the human female. Each year, more than 35,000 women in the US are diagnosed with endometrial cancer; and endometriosis affects up to 15% of reproductive aged women and often results in infertility. Further, inadequate preparation of the uterine lining during early gestation is thought to contribute to recurrent spontaneous pregnancy loss. It is clear that stem cells coordinate developmental and tissue renewal processes during the construction and maintenance of most organs. Yet there are almost no studies of stem cells in the development of the uterus, an organ that undergoes perhaps the most extensive proliferative changes and developmental remodeling in adult mammals. We hypothesize that endogenous endometrial stem/progenitor cells play a functional role in the cyclic changes within the uterus. Our experimental efforts involving bone marrow transplantation, peripheral blood cell infusions and parabiosis have collectively ruled out the likelihood that bone marrow contributes stem cells to uterine tissue architecture as has been suggested by others. Pulse- chase experiments using H2B:GFP transgenic mice and fate mapping studies revealed the identity of long-term label retaining cells (LRC) in the glandular epithelium and stromal compartment nearest the stromal:myometrial interface. A mouse model of endometrial regression and regeneration reveals that despite complete loss of the luminal epithelium following uterine decidualization, residual glandular tissue is sufficient to completely replace all epithelial tissue, an event that occurs in the absence of ovarian derived steroid hormones. Ongoing studies involving isolation and in vivo transplantation will test the stem cell activity of these putative stromal and epithelial adult stem cells. The long term goal of this proposal is to establish a framework with which to build upon as we begin to understand how endometrial stem cells contribute to normal uterine development and fertility, as well as to uterine diseases like endometriosis and endometrial cancer when stem cell function goes awry. PUBLIC HEALTH RELEVANCE: Dysfunction of the uterus is a common factor affecting fertility, the quality of life, and morbidity/mortality of the human female. Each year, more than 35,000 women in the United States are diagnosed with endometrial cancer (fourth most frequent among women), and endometriosis, another debilitating uterine disease that often results in severe pelvic pain and infertility, affects up to 15% of all reproductive aged women. Recurrent pregnancy loss, occurring in an estimated 25-60% of all mammalian conceptions, is thought to occur in part because of faulty preparation of the uterine lining during early pregnancy. Our understanding of these uterine pathologies, and in particular their etiology, is at best limited. Normal uterine function, and thus successful pregnancy, is dependent on normal cycles of endometrial growth, differentiation, regression (menses) and regeneration. We hypothesize that stem cells are responsible for maintenance of this uterine cycle and have proposed to isolate and characterize endometrial stem cells. The long-term goal of our proposed studies will be to demonstrate a causal link between faulty uterine stem cell function and gynecologic pathologies that impact negatively on fertility and quality of life in women.

描述（由申请人提供）：子宫疾病是影响人类女性生活质量和发病率/死亡率的极其常见的因素。每年，美国有超过35000名女性被诊断患有子宫内膜癌；子宫内膜异位症影响了多达15%的育龄妇女，并经常导致不孕。此外，在妊娠早期子宫内膜准备不足被认为是导致复发性自然流产的原因。很明显，干细胞在大多数器官的构建和维护过程中协调发育和组织更新过程。然而，几乎没有关于干细胞在子宫发育中的研究，子宫可能是成年哺乳动物中经历最广泛的增殖变化和发育重塑的器官。我们假设内源性子宫内膜干细胞/祖细胞在子宫内的循环变化中发挥功能作用。我们的实验包括骨髓移植，外周血细胞输注和异种共生，共同排除了骨髓为子宫组织结构提供干细胞的可能性，正如其他人所建议的那样。H2B:GFP转基因小鼠的脉冲追踪实验和命运定位研究揭示了腺体上皮和基质间室中长期标记保留细胞（LRC）的特性。子宫内膜退化和再生的小鼠模型显示，尽管子宫蜕膜后腔上皮完全丧失，但残留的腺组织足以完全取代所有上皮组织，这一事件发生在缺乏卵巢来源的类固醇激素的情况下。正在进行的研究包括分离和体内移植，将测试这些假定的基质和上皮成体干细胞的干细胞活性。这项建议的长期目标是建立一个框架，在此基础上，我们开始了解子宫内膜干细胞如何促进正常的子宫发育和生育，以及当干细胞功能出错时，子宫内膜异位症和子宫内膜癌等子宫疾病。