A 3Rs approach to investigate the feto-maternal interface: visualisation of pathogen and antibody in a 3D in vitro human placental model

研究胎儿-母体界面的 3R 方法：3D 体外人胎盘模型中病原体和抗体的可视化

• 批准号: 2610396
• 金额: --
• 依托单位: University of Liverpool
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2021
• 资助国家: 英国
• 起止时间: 2021 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2610396
• 关键词: 3Rs; approach; investigate; feto; maternal

Background: Immunisation during pregnancy is now recognised as an efficient approach to protect the fetus and/or the infant from life-threatening infection. However, the mechanisms underlying the transmission of pathogens and the transfer of passive immunity from the mother to the fetus remain obscure. The structure that lies at the interface between mother and fetal environment is the placenta, an intricate organ made up of cellular and vascular networks that serve the functions of kidney, lung, gut and liver altogether in order to promote fetal growth and viability. Owing to the ethical issues associated with the study of human pregnancy, a variety of in vivo, ex vivo and in vitro models have been developed. However, while the in vivo animal models fail to match the structural and/or functional properties of the human placenta, ex vivo human models are impractical, difficult to set up, of limited capability, and in vitro models lack physiological relevance by virtue of their monolayer and/or static set-up.Proposed solution: To address the caveats inherent to current experimental models of the human placenta, we propose to develop a novel and easy-to-set-up in vitro platform that will help reduce and/or replace the use of both murine and non-murine models. Our model will be validated through the analyses of placenta-blood barrier functions and cross-placental transport of pathogens and antibodies using a 3D microfluidic bioengineered platform i.e., the Organoplate (Mimetas).Experimental approach: Trophoblasts represent the most outer layer of the placenta whereby nutrients, chemical and gas feto-maternal exchanges are regulated. With the support of our industrial partner, we will develop an unprecedented trophoblast-based microfluidic dynamic model, that mimics the feto-maternal interface. This will be achieved using the commercially available and imaging-friendly 3-line OrganoPlate system (Mimetas BV), we will create a tubular culture system that mimics the three-dimensional, quasiphysiological environment where (fetal) endothelial cells will be luminally exposed to physiological levels of flow and co-cultured with abluminal trophoblasts to form a functional placental barrier. Our platform will be unique in that it will also offer real-time and high-throughput imaging capability.

背景：怀孕期间的免疫现在被认为是保护胎儿和/或婴儿免受危及生命的感染的有效方法。然而，病原体传播和被动免疫从母亲转移到胎儿的机制仍然不清楚。位于母亲和胎儿环境之间界面的结构是胎盘，这是一个由细胞和血管网络组成的复杂器官，共同服务于肾脏、肺、肠道和肝脏的功能，以促进胎儿的生长和活力。由于与人类妊娠研究相关的伦理问题，已经开发了多种体内、离体和体外模型。然而，虽然体内动物模型无法匹配人类胎盘的结构和/或功能特性，但体外人类模型不切实际、难以建立、能力有限，并且体外模型由于其单层和/或静态设置而缺乏生理相关性。建议的解决方案：为了解决当前人类胎盘实验模型固有的警告，我们建议开发一种新颖且易于建立的方法 体外平台将有助于减少和/或取代鼠类和非鼠类模型的使用。我们的模型将通过使用 3D 微流体生物工程平台（即 Organoplate (Mimetas)）分析胎盘-血液屏障功能以及病原体和抗体的跨胎盘转运来验证。实验方法：滋养层代表胎盘的最外层，通过它调节营养物质、化学物质和气体胎儿-母体交换。在我们的工业合作伙伴的支持下，我们将开发一种前所未有的基于滋养层的微流体动力学模型，该模型模仿胎儿-母体界面。这将使用市售且成像友好的 3 线 OrganoPlate 系统 (Mimetas BV) 来实现，我们将创建一个管状培养系统，模拟三维准生理环境，其中（胎儿）内皮细胞将在管腔内暴露于生理水平的流动，并与管腔滋养层细胞共培养，形成功能性胎盘屏障。我们的平台的独特之处在于它还将提供实时和高通量成像功能。