Stress-mediated trophoblast proliferation: adaptation or pathology?

项目摘要/摘要 对于许多孕妇来说，几乎没有有效的方法来治疗导致胎儿死亡的胎盘疾病。 胎儿结局和/或增加胎儿规划成人发病的风险。胎盘功能不良是一种 妊娠相关疾病的诱因，包括宫内生长受限(IUGR)和 子痫前期(PE)。尽管对怀孕和胎儿结局进行了数十年的研究，但事实并非如此 了解胎盘发育的基本生物学过程是如何失败的。异常滋养层细胞 细胞增殖和分化被认为是原因，但其病因尚不清楚。 在许多情况下，产科医生只能处理母亲的症状。尽管病毒的持续扩散 滋养层细胞存在于人和小鼠胎盘的整个妊娠过程中，人滋养层干细胞 最近才被发现的(TS)细胞被认为不会持续到早期发育之后。这 在我们对支持胎盘动态平衡和再生的机制的理解上留下了一个空白 有潜力，在怀孕后期。另一方面，小鼠的TS细胞的特征更好。他们已经被用来 作为支持滋养细胞增殖和分化的分子机制的研究模型， 从而有助于我们理解胎盘的发育和功能，尽管它们被认为是 在怀孕20天的情况下，E8.5耗尽。在许多器官中，组织特异性干/祖细胞是基础 动态平衡，并提供适应压力和伤害的能力。鉴定人类TS细胞可以提供 遇到并发症的孕妇中有8%-10%希望通过再生医学。按照这个逻辑，我们的 Lab发现滋养层细胞增殖增加，TS标记物eome的表达超过早期 并发现了以SCA-1为细胞表面的增殖、多潜能的TS样细胞 标记，在妊娠晚期的小鼠胎盘中。我们的主要假设是胎盘压力 滋养层细胞亚群的增殖潜能，我们认为这一群体对胎儿健康至关重要。 这项建议的目标是使用尖端的遗传和基因组技术来研究持续性TS 和SCA-1+滋养层细胞群在胎盘功能不全的背景下，并评估它们是否提供 小鼠胎盘是一种适应机制.我们将研究Sca-1(Ly6A)在小鼠滋养层细胞中的作用 以提供对适应性反应的洞察。此外，我们将比较小鼠TS的转录本与 新型人类TS细胞，集中在转录因子和细胞表面标志物上定义特异性 亚群，然后评估人类胎盘的适应性反应。最终，我们的工作将 确定胎盘的再生能力并帮助确定人类TS细胞在这一过程中的作用， 开发治疗妊娠胎盘相关疾病的新方法。

Project Summary/Abstract For many pregnancies, there are few effective ways to treat placental diseases that result in fetal demise, poor fetal outcome and/or increased risk of fetal programing of adult onset disease. Poor placental function is a contributing cause of pregnancy related diseases, including intrauterine growth restriction (IUGR) and preeclampsia (PE). Despite decades of research investigating pregnancy and fetal outcome, there is no true understanding of how the basic biological processes involved in placental development fail. Aberrant trophoblast cell proliferation and differentiation have been considered responsible, however the etiology is not understood and in many cases, obstetricians can only manage the mothers' symptoms. Although persistent proliferation of trophoblast cells occurs throughout gestation in both the human and mouse placentae, human Trophoblast Stem (TS) cells, which have just recently been identified, are not thought to persist beyond early development. This leaves a gap in our understanding of the mechanisms that support placental homeostasis and regenerative potential, later in pregnancy. Mouse TS cells, on the other hand, are better characterized. They have been used as an investigational model of the molecular mechanisms supporting trophoblast proliferation and differentiation, thereby contributing to our understanding of placental development and function, though they are thought to be depleted by E8.5 of a 20-day gestation. In many organs, tissue-specific stem/progenitor cells underlie homeostasis and provide an ability to adapt to stress and injury. Characterizing human TS cells could offer the 8-10% of pregnancies that encounter complications hope through regenerative medicine. Applying this logic, our lab identified increased trophoblast proliferation and expression of the TS marker, Eomes, beyond early development and have found a population of proliferative, multipotent TS-like cells using Sca-1 as a cell surface marker, in the late gestation mouse placenta. Our governing hypothesis is that placental stress confers proliferative potential to a sub-population of trophoblast, and we propose this population is critical to fetal health. The objectives of this proposal are to use cutting edge genetic and genomic techniques to study persistent TS and Sca-1+ trophoblast populations in the context of placental insufficiency and assess whether they provide the mouse placenta an adaptive mechanism. We will investigate the function of Sca-1(Ly6A) in mouse trophoblast to provide insight into the adaptive response. Additionally, we will compare the transcriptomes of mouse TS to the novel human TS cells, focusing on transcription factors and cell surface markers to define specific subpopulations to then evaluate the adaptive response of the human placenta. Ultimately, our work will determine the regenerative capacity of the placenta and aid in identifying the role human TS cells in this process, to develop new treatments for placental-related diseases of pregnancy.