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Placental models to support embryogenesis in vitro

支持体外胚胎发生的胎盘模型

基本信息

批准号：
10458580
负责人：
Magdalena Zernicka-Goetz
金额：
$ 116.55万
依托单位：
CALIFORNIA INSTITUTE OF TECHNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-30 至 2025-07-31
项目状态：
未结题

项目摘要

Most human pregnancies fail around the time of embryo implantation. Yet, the developmental mechanisms of this stage and how they go awry remain a mystery, because the implanted embryo is inaccessible to analysis within the body of the mother. Uncovering these mechanisms is of critical importance to overcome existing barriers to fertility and proper development. We have successfully generated systems that enable development of natural mouse and human embryos from pre- to post-implantation stages in vitro, and built stem cell-derived synthetic mouse embryos that can mimic some aspects of early post-implantation development. But approaches to study development continuously through the implantation stage and beyond gastrulation are lacking. We now propose to create a maternal-like environment that permits the long-term survival of both natural and synthetic mouse embryos. Our first challenge will be to engineer synthetic pre-implantation blastocysts with an expanded ability to generate the full range of correctly functioning extra-embryonic tissues. This breakthrough is expected to enable their implantation and development in utero, and may eventually transform approaches for engineering genetically modified mice. We will use these new tools to determine the precise cellular and molecular mechanisms that allow synthetic blastocysts to interact with the uterus in foster mothers. Our second challenge will be to generate artificial substrates, comprising hydrogels and proteins of the decidual extra-cellular matrix, to facilitate implantation events. In parallel, we will engineer synthetic placental-like structures for natural and synthetic embryo development using organoids derived from trophoblast and endometrial tissue. These systems would allow investigations and tracking of how insults to pre- and peri-implantation development, such as the exposure to pathogens, toxins, or teratogens affect subsequent development and life. Our third challenge will be to utilize these systems to discover the molecular events that accompany implantation. We will take advantage of our in vitro placental systems to investigate the chemical and physical signalling events that are key for development and determine how improved extra-embryonic contributions affect embryonic development until neurulation. These innovations will allow us to finally decipher a stage of development that is currently out of reach and of which our knowledge is greatly lacking. This will bring insight into a time of development when most pregnancies fail and thereby lead to advances in assisted reproductive technology; it will offer new screening routes for drug testing and environmental safety; and it will advance our knowledge of the use of stem cells in organogenesis and regenerative medicine.

大多数人类怀孕在胚胎植入时都会失败。然而，发育机制这个阶段的进展以及它们如何出错仍然是个谜，因为植入的胚胎无法进入分析母亲体内的情况。揭示这些机制对于克服这些问题至关重要生育和正常发育的现有障碍。我们已经成功生成了能够实现天然小鼠和人类胚胎从植入前到植入后阶段的体外发育，并建立干细胞衍生的合成小鼠胚胎可以模仿植入后早期的某些方面发展。但通过植入阶段持续研究发展的方法缺乏原肠胚以外的。我们现在建议创造一个像母亲一样的环境，让天然和合成小鼠胚胎的长期存活。我们的第一个挑战是设计合成的植入前囊胚具有扩展的能力，可以正确生成各种类型的囊胚有功能的胚胎外组织。这一突破有望使它们能够植入并子宫内发育，并可能最终改变转基因小鼠的工程方法。我们将使用这些新工具来确定允许合成的精确细胞和分子机制囊胚与养母的子宫相互作用。我们的第二个挑战是生成人工基质，包括水凝胶和蜕膜细胞外基质的蛋白质，以促进植入事件。与此同时，我们将为天然和合成胚胎设计合成胎盘样结构使用源自滋养层和子宫内膜组织的类器官进行开发。这些系统将允许调查和跟踪如何损害植入前和围植入期发育，例如暴露病原体、毒素或致畸物质会影响随后的发育和生命。我们的第三个挑战是利用这些系统来发现伴随植入的分子事件。我们将利用我们的体外胎盘系统研究化学和物理信号事件，这是关键发育并确定改善的胚胎外贡献如何影响胚胎发育直至神经形成。这些创新将使我们最终破译当前的发展阶段遥不可及，我们的知识也非常缺乏。这将带来对发展时代的洞察大多数妊娠失败，从而导致辅助生殖技术的进步；它将提供药物检测和环境安全的新筛选途径；它将增进我们对干细胞在器官发生和再生医学中的应用。