Decidual Fibroblast Differentiation and Human Implantation

着床是人类早期发育的重要部分，因为这一过程中的异常可能 导致流产、不孕和妊娠障碍，包括胎儿生长受限和先兆子痫。 成功的着床需要雌激素(E2)诱导的子宫内膜细胞生长和孕酮(P)- 诱导分化(蜕膜化)。IGF-II是一种主要的细胞母细胞(CTB)产物，调节 母体蜕膜调节因子对CTB侵袭的影响我们最近发现IGF-II和其他CTB产品 还可诱导蜕膜成纤维细胞的免疫表型，这种表型依赖于P对这些细胞作用的程度 细胞。例如，趋化因子和血管生成因子CXCL1(GRO1)在 IGF-II对蜕膜化(但不是非蜕膜化)基质成纤维细胞的作用。它的同源受体CXCL2是 CXCL1/CXCL2对在母体滋养细胞中的重要作用 互动。子宫内膜异位症患者的特点是子宫内膜P反应受限。 与不孕不育和不良妊娠结局有关的妇科疾病，据信主要是由于 部分，子宫内膜对P-耐药。我们假设不完全的P作用于子宫内膜间质 成纤维细胞对入侵的CTB的旁分泌免疫反应受损，并可能使女性倾向于 这种疾病导致不孕不育和不良的妊娠结局。我们的具体目标是：目标1.澄清 子宫内膜异位症患者子宫内膜间质成纤维细胞耐药机制的研究 关注P调节基因和FOXO1 A，这是基质成纤维细胞命运的关键决定因素。目标2.目标 蜕膜-滋养层细胞相互作用及IGF-II信号转导通路在早孕免疫应答中的作用 患有和不患有子宫内膜异位症的妇女子宫内膜间质成纤维细胞。目标3.确定是否 CXCL1由蜕膜化的间质成纤维细胞产生，对入侵的滋养层细胞做出反应，影响 人滋养层细胞的增殖、分化/侵袭和血管表型的获得。成功 拟议实验的完成有望加强我们对以子宫内膜为基础的 子宫内膜异位症患者不孕症及不良妊娠结局与发育的关系 与这种疾病相关的新的诊断和治疗方法。我们对这个中心的参与极大地 通过我们与所有调查人员的互动和对其宝贵核心设施的访问，使其更加丰富。

Implantation is an important part of early human develoment, because abnormalities in this process can lead to miscarriage, infertility, and pregnancy disorders, including fetal growth restriction and pre-eclampsia. Successful implantation requires estradiol (E2)-induced endometrial cellular growth and progesterone (P)- induced differentiation (decidualization). IGF-II is a major cytoytophoblast (CTB) product that regulates maternal decidual modulators of CTB invasion. We have recently found that IGF-II and other CTB products also elicit an immune phenotype in decidual fibroblasts that is dependent on the extent of P action on these cells. For example, the chemokine and angiogenic factor CXCL1 (GRO1) is up-regulated in response to IGF-II action on decidualized (but not non-decidualized) stromal fibroblasts. Its cognate receptor, CXCL2, is abundantly expressed in CTB, suggesting an important role for CXCL1/CXCL2 pair in maternal-trophoblast interactions. Limited P response in endometrium is a characteristic of women with endometriosis, a gynecologic disorder associated with infertility and poor pregnancy outcome, believed to be due, in large part, to P-resistance in the endometrium. We hypothesize that incomplete P action on endometrial stromal fibroblasts compromises their paracrine immune response to invading CTBs and may predispose women with this disorder to infertility and poor pregnancy outcome. Our specific aims are: Aim 1. To elucidate mechanisms underlying P-resistance in endometrial stromal fibroblasts from women with endometriosis, with a focus on P-regulated genes and FOXO1 A, a key determinant of stromal fibroblast cell fate. Aim 2. To elucidate decidua-trophoblast interactions and IGF-II signaling pathways in the immune response of endometrial stromal fibroblasts in women with and without endometriosis. Aim 3. To determine whether CXCL1, produced by the decidualized .stromal fibroblast in response to the invading trophoblast, affects human trophoblast proliferation, differentiation/invasion and acquisition of a vascular phenotype. Successful completion of the proposed experiments promises to strengthen our understanding of endometrial-based infertility and poor pregnancy outcomes in women with endometriosis and to contribute to the development of novel diagnostics and therapeutics associated with this disorder. Our participation in this Center is greatly enriched by our interactions with all investigators and access to its valuable core facilities.