Placental models to support embryogenesis in vitro

支持体外胚胎发生的胎盘模型

• 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
• 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
• 来源: https://reporter.nih.gov/project-details/10458580
• 关键词: Affect; Assisted Reproductive Technology; Chemicals; Development; Developmental Biology; Disease; Embryo; Embryonic Development; Endometrial; Engineering; Environment; Event; Exposure to; Extracellular Matrix; Fertility; Fostering; Genetic Engineering; Human; Hydrogels; Implant; In Vitro; Investigation; Knowledge; Lead; Life; Light; Modeling; Molecular; Mothers; Mus; Organogenesis; Organoids; Pregnancy; Proteins; Regenerative Medicine; Reproductive Biology; Research; Route; Safety; Signal Transduction; Structure; System; Teratogens; Time; Tissues; Toxin; Uterus; blastocyst; clinically relevant; critical period; drug testing; gastrulation; implantation; improved; in utero; innovation; insight; medication safety; natural Blastocyst Implantation; pathogen; pregnancy failure; preimplantation; screening; stem cell biology; stem cells; tool; trophoblast

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.

大多数人的怀孕在胚胎植入时失败。但是，发展机制 在这个阶段以及它们如何出现仍然是一个谜，因为植入的胚胎是无法访问的 母亲体内的分析。发现这些机制对于克服至关重要 现有的生育障碍和适当的发展。我们已经成功地生成了启用的系统 自然小鼠和人类胚胎从体外植入阶段到植入后阶段的发展，并建造 干细胞衍生的合成小鼠胚胎可以模仿早期植入后的某些方面 发展。但是在植入阶段不断研究发展的方法和 缺乏胃口。现在，我们建议创建一个类似母体的环境，以允许 天然和合成小鼠胚胎的长期生存。我们的第一个挑战是工程师 合成植入前胚泡具有扩展的能力，可以正确产生完整的范围 功能外胚外组织。预计这一突破将使他们的植入和 子宫内发育，最终可能会改变工程转基因小鼠的方法。 我们将使用这些新工具来确定允许合成的精确的细胞和分子机制 胚泡与寄养母亲的子宫相互作用。我们的第二个挑战将是产生人造 底物，包括判断外基质的水凝胶和蛋白质，以促进植入 事件。同时，我们将设计自然和合成胚胎的合成胎盘状结构 使用源自滋养细胞和子宫内膜组织的类器官发育。这些系统将允许 调查和跟踪侮辱前和植入周期发展的侮辱，例如暴露 病原体，毒素或畸胎组会影响随后的发育和生命。我们的第三个挑战将是 利用这些系统发现植入植入的分子事件。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的关键 开发并确定改进的外交贡献如何影响胚胎开发 直到神经。这些创新将使我们最终破译一个目前的发展阶段 遥不可及，我们的知识极大地缺乏。这将使您洞察发展时期 当大多数怀孕失败并因此导致辅助生殖技术的进步；它将提供 用于药物测试和环境安全的新筛选途径；它将提高我们对 在器官发生和再生医学中使用干细胞。