Department of Genetics, Yale School of Medicine, Yale University, New Haven, CT, 06510, USA; Yale Stem Cell Center, Yale University, New Haven, CT 06520, USA.
Max Planck Institute of Molecular Cell Biology and Genetics, Pfotenhauerstrasse 108, 01307 Dresden, Germany.
Semin Cell Dev Biol. 2022 Nov;131:44-57. doi: 10.1016/j.semcdb.2022.05.023. Epub 2022 Jun 11.
How cells build embryos is still a major mystery. Many unresolved questions require the study of the processes that pattern and shape the embryo in live specimens, in toto, across spatial and temporal scales. In mammalian embryogenesis, this remains a major challenge as the embryo develops in utero, precluding easy accessibility. For human embryos, technical, ethical and legal limitations further hamper the in-depth investigation of embryogenesis, especially beyond gastrulation stages. This has resulted in an over-reliance on model organisms, particularly mice, to understand mammalian development. However, recent efforts show critical differences between rodent and primate embryos, including timing, architecture and transcriptional regulation. Thus, a human-centric understanding of embryogenesis is much needed. To empower this, novel in vitro approaches, which coax human pluripotent stem cells to form embryonic organoids that model embryo development, are pivotal. Here, we summarize these emergent technologies that recapitulate aspects of human development "in a dish". We show how these technologies can provide insights into the molecular, cellular and morphogenetic processes that fuel the formation of a fully formed fetus, and discuss the potential of these platforms to revolutionize our understanding of human development in health and disease. Despite their clear promise, we caution against over-interpreting the extent to which these in vitro platforms model the natural embryo. In particular, we discuss how fate, form and function - a tightly coupled trinity in vivo, can be disconnected in vitro. Finally, we propose how careful benchmarking of existing models, in combination with rational protocol design based on an increased understanding of in vivo developmental dynamics and insights from mouse in vitro models of embryo development, will help guide the establishment of better models of human embryo development.
细胞如何构建胚胎仍然是一个主要的谜团。许多悬而未决的问题需要研究胚胎在活体标本中的模式形成和形态形成过程，需要跨越时空尺度进行研究。在哺乳动物胚胎发生中，由于胚胎在子宫内发育，难以接近，因此这仍然是一个主要挑战。对于人类胚胎来说，技术、伦理和法律限制进一步阻碍了胚胎发生的深入研究，特别是在原肠胚形成阶段之后。这导致人们过度依赖模式生物，特别是小鼠，来理解哺乳动物的发育。然而，最近的研究努力表明，啮齿动物和灵长类动物胚胎之间存在关键差异，包括时间、结构和转录调控。因此，非常需要从人类为中心的角度来理解胚胎发生。为了实现这一目标，新兴的体外方法至关重要，这些方法可以诱导人类多能干细胞形成模拟胚胎发育的胚胎类器官。在这里，我们总结了这些新兴技术，这些技术可以在体外模拟人类发育的各个方面。我们展示了这些技术如何为研究驱动完全形成胎儿形成的分子、细胞和形态发生过程提供新的见解，并讨论了这些平台在健康和疾病中革命性地理解人类发育的潜力。尽管这些技术有明显的优势，但我们警告不要过度解释这些体外平台在多大程度上模拟了自然胚胎。特别是，我们讨论了命运、形态和功能——在体内紧密耦合的三位一体，如何在体外分离。最后，我们提出了如何通过对现有模型进行仔细的基准测试，结合对体内发育动力学的深入理解以及来自小鼠体外胚胎发育模型的见解，基于合理的方案设计，来指导更好的人类胚胎发育模型的建立。
