Placental models to support embryogenesis in vitro

大多数人类妊娠在胚胎植入前后失败。然而，发展机制 这一阶段以及它们是如何出错的仍然是一个谜，因为植入的胚胎无法接触到 母亲体内的分析。揭示这些机制对于克服这些机制至关重要 生育率和适当发展方面的现有障碍。我们已成功生成支持以下功能的系统 自然小鼠和人类胚胎从植入前到植入后的体外发育，并建立了 干细胞衍生的合成小鼠胚胎可以模拟植入后早期的某些方面 发展。但通过植入阶段持续研究发育和 缺乏超原肠化。我们现在建议创造一个母性的环境，允许 自然和合成小鼠胚胎的长期存活。我们的第一个挑战将是设计 人工合成的植入前胚泡具有扩展的能力，能够产生全面的正确 正常运作的胚胎外组织。这一突破有望使它们能够植入和 在子宫内发育，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精确的细胞和分子机制，使合成 在养母体内，胚泡与子宫相互作用。我们的第二个挑战将是产生人工智能 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。同时，我们将为天然胚胎和合成胚胎设计合成的胎盘状结构。 使用从滋养细胞和子宫内膜组织中提取的有机化合物进行开发。这些系统将允许 调查和跟踪如何侮辱植入前和围产期的发育，如暴露 病原体、毒素或致畸物质会影响后续的发育和生活。我们的第三个挑战将是 利用这些系统来发现伴随着植入的分子事件。我们会利用这个优势 我们的体外胎盘系统来研究化学和物理信号事件，这些事件是 发展和确定改善的胚胎外贡献如何影响胚胎发育 直到神经形成。这些创新将使我们能够最终破译目前的发展阶段 这是遥不可及的，而我们对此所知甚少。这将带来对发展时代的洞察 当大多数怀孕失败，从而导致辅助生殖技术的进步时，它将提供 为药物测试和环境安全提供新的筛查途径；它将增进我们对 干细胞在器官发生和再生医学中的应用。

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.