The intrauterine environment and human early placental development; a new paradigm for the pathophysiology of complications of pregnancy

宫内环境与人类早期胎盘发育；

• 批准号: MR/L020041/1
• 负责人: Graham Burton
• 金额: $ 50.9万
• 依托单位: University of Cambridge
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2014
• 资助国家: 英国
• 起止时间: 2014 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FL020041%2F1
• 关键词: intrauterine; environment; human; early; placental

Adverse outcomes of pregnancy, such as growth restriction, stillbirth, pre-eclampsia and prematurity, place considerable economic and emotional burdens on society. They cause significant morbidity and mortality; in the UK 10-12% of pregnancies miscarry and there are approximately 4,000 stillbirths each year. A further 10-12% suffer growth restriction, which predisposes to an increased risk of cardiovascular and other diseases in adult life. The causes of these complications are complex, and despite much research their incidence has not changed substantially over the last 50 years; indeed, the incidence of low birth weight is increasing in the USA. This research programme takes a fresh and innovative approach to understanding their cause by focusing on a key unifying feature, impaired early development of the placenta. The placenta nourishes and protects the embryo, and so needs to develop rapidly after fertilisation. The overall aim is to investigate how that early development is stimulated, and how perturbations in the uterine environment lead to aberrant placentation. A more complete understanding of these critical events will ultimately facilitate interventions being devised that prevent complications being initiated, rather than attempting to treat them once established.Our previous research supported by the MRC, transformed our understanding of the environment inside the uterus in early pregnancy. For many years it had been assumed that placental development was a continuum across gestation, but we demonstrated that it occurs in two very distinct phases. During the first 10-12 weeks, the placenta receives nutritional support from the glands lining the uterus, rather than from the maternal circulation as it does later. The glands provide essential nutrients, but also secrete proteins that can act as powerful stimulants to growth. Indeed, in some species, such as the sheep, the placenta sends signals to the glands to produce more of these proteins, and so enhances its own growth. The uterus therefore plays a much more dynamic role in supporting the first third of pregnancy than previously anticipated, creating a unique highly stimulatory microenvironment.Our goal is to fully characterise that environment in the human, understand how it is regulated and investigate its impact on proliferation and differentiation of placental cells. The first aim is to identify the range of proteins secreted by the uterus using the latest sequencing techniques to analyse gene expression in samples of the lining of the uterus. We have recently applied the same technique to progenitor cells isolated from the early placenta, and so will able to identify potential growth factor/receptor interactions. The impact of these interactions on progenitor cell behaviour will then be tested in vitro. The second aim is to explore the signals coming from the placenta that might increase or alter the secretions. The third aim is to investigate using genetically modified mice whether metabolic stress alters secretions and impairs fetal growth. We will also determine whether stresses in humans such as obesity and diabetes, that are associated with adverse obstetric outcomes, reduce the effectiveness of these mechanisms and impair placental development. Finally, we will determine whether development of the uterus is compromised in offspring who are born growth restricted, resulting in intergenerational effects on birth weight.It is anticipated that the results will have major implications for reproductive and public health medicine. Understanding the fetal-maternal dialogue during early pregnancy will help to develop novel interventions to optimise placental development. Equally, an appreciation of the impact of metabolic and other stresses on uterine function during early pregnancy may lead to improved peri-conceptional care. In the longer term, having healthier normal birth weight babies will help to reduce the burden of chronic disease in adulthood.

妊娠的不良后果，如生长受限、死产、先兆子痫和早产，给社会带来相当大的经济和情感负担。它们会导致严重的发病率和死亡率；在英国，10%-12%的孕妇流产，每年大约有4000例死产。另有10%-12%的人患有生长受限，这容易增加成年后患心血管疾病和其他疾病的风险。这些并发症的原因很复杂，尽管进行了大量研究，但它们的发生率在过去50年中并没有发生实质性变化；事实上，在美国，低出生体重的发生率正在增加。这项研究计划采取了一种新鲜和创新的方法来了解他们的原因，重点是一个关键的统一特征，胎盘的早期发育受损。胎盘滋养和保护胚胎，因此需要在受精后迅速发育。总体目标是调查早期发育是如何被刺激的，以及子宫环境的扰动是如何导致异常胎盘的。对这些关键事件的更完整的了解最终将有助于设计预防并发症的干预措施，而不是一旦确定就试图治疗它们。我们之前的研究得到了MRC的支持，改变了我们对怀孕早期子宫内环境的理解。多年来，人们一直认为胎盘发育是一个贯穿整个妊娠的连续体，但我们证明了它发生在两个非常不同的阶段。在最初的10-12周内，胎盘从子宫内壁的腺体获得营养支持，而不是像后来那样从母体循环中获得营养支持。腺体提供必要的营养，但也会分泌蛋白质，这些蛋白质可以对生长起到强大的刺激作用。事实上，在一些物种中，例如绵羊，胎盘向腺体发送信号，以产生更多的这些蛋白质，从而促进自身的生长。因此，子宫在支持妊娠前三分之一方面的作用比之前预期的要活跃得多，创造了一个独特的高度刺激的微环境。我们的目标是全面描述人类的这种环境，了解它是如何调节的，并研究它对胎盘细胞增殖和分化的影响。第一个目标是使用最新的测序技术来分析子宫衬里样本中的基因表达，以确定子宫分泌的蛋白质范围。我们最近将同样的技术应用于从早期胎盘分离的祖细胞，因此将能够识别潜在的生长因子/受体相互作用。这些相互作用对祖细胞行为的影响将在体外进行测试。第二个目标是探索来自胎盘的信号，这些信号可能增加或改变分泌物。第三个目的是利用转基因小鼠研究代谢应激是否会改变分泌并损害胎儿生长。我们还将确定人类的压力，如肥胖和糖尿病，是否与不利的产科结果相关，降低这些机制的有效性，并损害胎盘发育。最后，我们将确定出生发育受限的后代的子宫发育是否受到影响，从而对出生体重产生代际影响。预计结果将对生殖和公共卫生医学产生重大影响。了解怀孕早期胎儿-母亲的对话将有助于开发新的干预措施，以优化胎盘发育。同样，在怀孕早期认识到代谢和其他压力对子宫功能的影响可能会导致改善围产期护理。从长远来看，拥有更健康的正常出生体重的婴儿将有助于减轻成年后慢性疾病的负担。

项目成果

Long-term, hormone-responsive organoid cultures of human endometrium in a chemically defined medium.

• DOI: 10.1038/ncb3516
• 发表时间: 2017-05
• 期刊: Nature cell biology
• 影响因子: 21.3
• 作者: Turco MY;Gardner L;Hughes J;Cindrova-Davies T;Gomez MJ;Farrell L;Hollinshead M;Marsh SGE;Brosens JJ;Critchley HO;Simons BD;Hemberger M;Koo BK;Moffett A;Burton GJ
• 通讯作者: Burton GJ

RNA-seq reveals conservation of function among the yolk sacs of human, mouse, and chicken

• DOI: 10.1073/pnas.1702560114
• 发表时间: 2017-06-13
• 期刊: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• 影响因子: 11.1
• 作者: Cindrova-Davies, Tereza;Jauniaux, Eric;Charnock-Jones, D. Stephen
• 通讯作者: Charnock-Jones, D. Stephen

Long-term, hormone-responsive organoid cultures of human endometrium in a chemically defined medium

在化学成分确定的培养基中对人子宫内膜进行长期激素响应类器官培养

• DOI: 10.17863/cam.10121
• 发表时间: 2017
• 作者: Turco M

RNA-Seq reveals changes in human placental metabolism, transport and endocrinology across the first-second trimester transition.

• DOI: 10.1242/bio.058222
• 发表时间: 2021-06-15
• 期刊: Biology open
• 影响因子: 2.4
• 作者: Prater M;Hamilton RS;Wa Yung H;Sharkey AM;Robson P;Abd Hamid NE;Jauniaux E;Charnock-Jones DS;Burton GJ;Cindrova-Davies T
• 通讯作者: Cindrova-Davies T

Trophoblast organoids as a model for maternal-fetal interactions during human placentation.

滋养层类器官作为人类胎盘期间母胎相互作用的模型。

• DOI: 10.17863/cam.34021
• 发表时间: 2018
• 作者: Turco M