Development of endometrial/myometrial organoids to study disorders of pregnancy and parturition

在所有临床确认的妊娠中，约有15%以流产告终，大多在妊娠12周之前。除了身体创伤（疼痛、出血和感染）外，每次流产都增加了严重的心理疾病（抑郁症、创伤后应激障碍和自杀）和未来持续妊娠的产科并发症的风险，最重要的是早产。在全球范围内，早产（定义为在妊娠37周前分娩婴儿）影响了5-18%的活产婴儿，尽管其发生率因种族和社会经济因素而异。早产是新生儿发病和死亡的最重要原因，特别是“非常早产”婴儿（妊娠32周前出生的婴儿）。迄今为止，对流产或早产都没有有效的预防性治疗方法。临床治疗主要局限于黄体酮，这是一种90年前发现的激素，但其有效性仍存在争议。这些重要的生殖疾病以及其他疾病仍未得到解决，主要是因为科学动物模型未能准确地代表人类的特定特征。虽然动物模型（如小鼠）被广泛使用，但它们并不能近似于人类妊娠，也没有产生足够的机制见解来对临床实践产生明显的影响。大多数模式生物，如小鼠、大鼠和豚鼠，与人类相比，具有根本不同的生殖策略，以及解剖学上不同的子宫。灵长类动物，特别是旧大陆的猴子是一个例外，但这些模型价格昂贵，在伦理上有争议，并且需要专门的设施。为了解决人类子宫疾病的知识差距，我们最近建立了子宫内膜组装体，由实验室组装的培养物组成，其中包含子宫内膜的主要细胞。这些组合体可以模拟与生殖失败相关的不同病理状态，例如与人类研究胚胎共培养。这个模型还没有包含子宫的主要肌肉子宫肌层。人类胚胎着床是深层的，涉及到内肌层的破坏，也称为连接带（JZ）。研究表明，JZ对着床和生育很重要，它是子宫对怀孕反应的重要组成部分。这项提议的目的是通过增加肌肉层来进一步改善我们的装配体模型，以创造一种新的人类怀孕模型。这样，在考虑人类早期妊娠和相关疾病的研究时，我们应该能够通过提供科学上优越的模型来取代动物实验。我们还将创建一个新的年度虚拟会议，供世界各地试图用类器官技术取代动物实验的科学团体参加。随着这一富有成效的研究领域取得进展，我们将交换有价值的、最先进的方法，并将这些方法以一种形式记录下来，供有兴趣采用这些技术的研究人员随时使用。我们已经得到了十多个世界领先集团的同意，同意参加这一倡议。随着会议的建立，我们将努力招募更多的集团。

Approximately 15% of all clinically recognised pregnancies end in miscarriage, mostly before 12 weeks of gestation. Apart from physical trauma (pain, bleeding, and infection), each miscarriage compounds the risk of significant psychological morbidity (depression, post-traumatic stress disorder, and suicide) and obstetrical complications in a future ongoing pregnancy, foremost preterm birth. Globally, preterm birth, defined as delivery of a baby before 37 completed weeks' gestation, affects 5-18% of live births, although the incidence varies dependent on ethnicity and socioeconomic factors. Preterm birth is the single most important cause of neonatal morbidity and mortality, especially in "very preterm" infants (those born before 32 weeks' gestation). To date, there are no effective preventative treatments for either miscarriage or preterm birth. Clinical management is largely confined to progesterone, a hormone discovered > 90 years ago, but its effectiveness remains contentious. These important reproductive disorders, together with others, remain unresolved largely as a consequence of scientific animal models failing to accurately represent human specific traits. Although animal models, such as mice, are widely used, they do not approximate human pregnancy, nor have they yielded sufficient mechanistic insights to impact demonstrably on clinical practice. Most model organisms such as the mouse, rat and guinea pig, have fundamentally different reproductive strategies when compared to humans, as well as anatomically distinct uteri. Primates, and more specifically Old-World monkeys, are an exception but these models are expensive, ethically contentious, and require specialised facilities. To address the knowledge gap in human uterine diseases, we recently established endometrial assembloids, consisting of lab assembled cultures that contain the main cells of the lining of the uterus.These assembloids can be manipulated to mimic different pathological states associated with reproductive failure, exemplified by co-culturing with human research embryos. This model does not yet contain the main muscle of the uterus the myometrium. Human embryo implantation is deep and involves disruption of the inner myometrial layer, also termed the junctional zone (JZ). Studies have demonstrated that the JZ is important for implantation and fertility and that it is a crucial component of the uterine response to pregnancy. The aim of this proposal is to improve our assembloid model further by the addition of this muscle layer to create a new model of human pregnancy. In doing so we should be able to replace animal experiments by offering a scientifically superior model when considering studies in early human pregnancy and associated diseases. We will also create a new, annual virtual conference, for scientific groups around the world currently attempting to replace animal experiments by using organoid technologies. We will exchange valuable state-of-the-art methods as this productive area of research makes advances and document these methods in a form that can be readily used by researchers interested in adopting these techniques. We already have agreement from over ten of the worlds leading groups to participate in this initiative and we will endeavour to recruit further groups as the conferences become more established.