Stress-mediated trophoblast proliferation: adaptation or pathology?

项目总结/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/或成人发病疾病的胎儿编程风险增加。胎盘功能差是一种 导致妊娠相关疾病的原因，包括宫内生长受限（IUGR）， 先兆子痫（PE）。尽管数十年来对妊娠和胎儿结局的研究， 了解胎盘发育中的基本生物过程是如何失败的。异常滋养层 细胞的增殖和分化被认为是原因之一，但病因尚不清楚 在许多情况下，产科医生只能控制母亲的症状。虽然持续扩散， 滋养层细胞在整个妊娠期出现在人类和小鼠的胎盘中，人类滋养层干细胞 (TS)最近才被发现的细胞，被认为在早期发育之后不会持续存在。这 在我们对支持胎盘稳态和再生机制的理解中留下了空白， 潜在的，在怀孕后期。另一方面，小鼠TS细胞更好地表征。池使用 作为支持滋养层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20天的妊娠期内被E8.5耗尽。在许多器官中，组织特异性干/祖细胞是 并提供适应压力和损伤能力。表征人类TS细胞可以提供 8-10%遇到并发症的怀孕希望通过再生医学。根据这一逻辑，我们 实验室发现滋养层细胞增殖和TS标记物Eomes的表达增加，超过早期， 发展，并发现了一群增殖的多能TS样细胞，使用Sca-1作为细胞表面 标记物，在妊娠晚期小鼠胎盘中。我们的主要假设是胎盘压力 滋养层细胞亚群的增殖潜力，我们认为这个群体对胎儿健康至关重要。 这项建议的目的是利用最先进的遗传和基因组技术来研究持久性TS 和Sca-1+滋养层细胞群，并评估它们是否提供了 小鼠胎盘的适应机制。本研究旨在探讨Sca-1（Ly 6A）在小鼠滋养细胞中的功能 以提供对适应性反应的深入了解。此外，我们将比较小鼠TS的转录组与 新的人TS细胞，专注于转录因子和细胞表面标记，以定义特异性 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， 开发治疗妊娠期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.