The impact of metformin on early placental development and metabolism

健康的妊娠是健康人群的基础，但很少有改善妊娠结局的治疗方法。特别是很少有药物可以预防早孕频繁并发症，如流产和早发性先兆子痫。一些证据表明二甲双胍可能有助于预防这两种结果。二甲双胍是一种廉价、全球可用的药物，几乎没有严重的副作用。如果它被证明能有效预防流产或先兆子痫，那么这将是早期妊娠护理的一个重大突破，它可以提供给全球有风险的妇女。流产和先兆子痫都可能是由胎盘发育早期的问题引起的，胎盘在整个怀孕过程中一直支持着发育中的婴儿。在怀孕开始时胎盘发育的微小变化可能会导致后来的灾难性失败，因此最佳的胎盘形成对于降低后期并发症的风险至关重要。我们的目标是研究二甲双胍是否可以提高这些早期阶段胎盘正确着床的机会。我们之前的研究表明，二甲双胍可能会抵消胎盘发育过程中过多的氧气或葡萄糖的影响，从而提高胎盘能够最有效地支持胎儿生长的机会。然而，也有人担心二甲双胍可能会在怀孕后期对胎盘有害。我们的荟萃分析表明，接受二甲双胍治疗的母亲更有可能生下较小的婴儿，这表明二甲双胍可能会限制妊娠晚期胎儿的生长。证据还表明，这些婴儿可能会在以后的生活中积累更多的脂肪组织。我们以前的研究表明，二甲双胍改变了胎盘产生能量的方式，以及它用来支持发育中的婴儿的燃料。鉴于这些发现，在考虑二甲双胍是否可以安全有效地用于预防流产或先兆子痫之前，需要仔细评估二甲双胍对发育中胎盘的确切作用方式。我们将详细研究二甲双胍是否可能改变能量产生、生长和不同细胞类型的形成过程，这些过程对胎盘的正常发育至关重要。我们将利用妊娠研究中一个令人兴奋的新进展，即迷你“胎盘盘”（滋养层类器官）。这些微小的细胞簇分裂并形成胎盘的所有主要细胞类型，使我们能够在实验室中研究这些过程。我们还将使用已建立的人滋养层干细胞系来优化我们的实验，验证我们的发现，并进行额外的分析。我们的关键实验将包括测量临床相关剂量的二甲双胍对早期胎盘生长和发育的影响，特别是与母亲循环建立接触的细胞的形成。我们假设二甲双胍会影响这些细胞分化和形成足够连接的能力。我们还将在我们的实验性胎盘模型中改变氧气水平和葡萄糖水平。胎盘的发育最初是在子宫内非常低的氧气水平下自然发生的，暴露于母亲血液中过量的氧气被认为是早期妊娠并发症的原因。我们将研究二甲双胍是否可以通过阻断自由基的形成来防止过量氧气对发育细胞的损害。我们还将研究早期发育期间葡萄糖浓度的影响，以及在二甲双胍和生理性低葡萄糖水平的情况下是否可以维持细胞能量平衡。我们的首要目标是确定二甲双胍是否是一种安全有效的药物，以帮助预防早期妊娠并发症。

Healthy pregnancies are fundamental to healthy populations, but very few therapies to improve pregnancy outcomes are available. In particular there are few drugs that can prevent frequent complications of early pregnancy, such as miscarriage and early-onset pre-eclampsia. Some evidence suggests metformin might help to prevent both of these outcomes. Metformin is a cheap, globally available drug, with few serious side-effects. If it were shown to be effective for preventing miscarriage or pre-eclampsia, then this would be a major breakthrough for early pregnancy care and it could be made available to women at risk globally. Both miscarriage and pre-eclampsia can be caused by problems very early in the development of the placenta, which supports the developing baby the whole way through pregnancy. Tiny variations in placental development at the start of pregnancy can lead to catastrophic failure later on, so optimal establishment of placentation is crucial to reduce the risk of later complications. We aim to investigate whether metformin improves the chances of the placenta establishing correctly during these early stages. Our previous work suggests that metformin may counteract the impact of too much oxygen or glucose during placental development and thus improve the chances of the placenta being able to support the growing fetus most effectively.However there is also concern metformin may be detrimental to the placenta later in pregnancy. Our meta-analysis suggests that mothers treated with metformin are more likely to give birth to smaller babies, suggesting that metformin may restrict fetal growth during late pregnancy. Evidence also suggests that these babies may go on to accumulate more fat tissue in later life. Our previous work shows that metformin alters the way that the placenta generates energy and the fuels that it uses to support the developing baby. In view of these findings, the precise ways that metformin acts on the developing placenta need careful evaluation before considering whether it could safely and effectively be used to prevent miscarriage or pre-eclampsia.We will examine in detail whether metformin might alter the processes of energy production, growth, and the formation of different cell types that are all vital to normal placental development. We will take advantage of an exciting new development in pregnancy research, the mini 'placenta-in-a-dish' (trophoblast organoids). These tiny cell clusters divide and form into all the major cell types of the placenta, allowing us to study these processes in the laboratory. We will also use established human trophoblast stem cell lines to optimise our experiments, validate our findings, and perform additional assays.Our key experiments will involve measuring the effect of metformin at clinically-relevant doses on the growth and development of the early placenta, in particular the formation of cells that establish contact with the mother's circulation. We hypothesise that metformin will influence the ability of these cells to differentiate and form adequate connections. We will also alter oxygen levels and glucose levels in our experimental placenta-in-a-dish models. Placental development occurs naturally at very low oxygen levels inside the womb initially, and exposure to excess oxygen from the mother's blood is thought to be a cause of early pregnancy complications. We will investigate whether metformin can prevent damage to the developing cells from excess oxygen, by blocking the formation of free radicals. We will also look at the impact of glucose concentrations during early development and whether cell energy balance can be maintained in the presence of both metformin and physiologically low glucose levels. Our over-arching aim is to establish whether metformin could be a safe and effective drug to help prevent early pregnancy complications.