Human gastruloids: an in vitro system for the study of human gastrulation

人类原肠胚：用于研究人类原肠胚形成的体外系统

基本信息

批准号：
MR/R017190/1
负责人：
Benjamin Steventon
金额：
$ 45.56万
依托单位：
University of Cambridge
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2018
资助国家：
英国
起止时间：
2018 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=MR%2FR017190%2F1
关键词：
Human gastruloids vitro system study

项目摘要

The discovery that mouse and human Embryonic Stem Cells (ESCs) can be coaxed in vitro to form tissues and organs has raised expectations that the associated protocols for guided differentiation in culture will provide a basis for the successful development of a rational Regenerative Medicine. However it is early days. At the moment the most successful experiments are being done with mouse ESCs because they allow a wide range of experiments in a well understood and standardized system. Also, while there are protocols that can generate organ like structures -called organoids- in vitro, the protocols are neither robust nor reproducible enough to be if much use. A reason for this is that while we have made great advances in our understanding of the genes that control the emergence of specific cell types, we have little understanding of how the expression of these genes is translated into the three dimensional structures that characterize tissues and organs. Understanding this requires a user friendly three dimensional experimental system that mimics the embryo. The situation is even more challenging in the case of human tissues and organs since, in this case, we have very little insight on the development of human embryos and negligible knowledge of their cellular and molecular underpinning. Making progress in this important area of research is also limited by obvious ethical issues and regulations associated with the use of human embryos. ESCs provide an alternative experimental system but current studies with human ESCs restrict themselves to adherent cultures or use the mouse and mouse ESCs as a standard reference for human biology because of its superficial similarities in the underlying developmental processes. However, there are significant differences between the two species that, when considered in detail, highlight the need for a better understanding of the specific cellular and molecular features underlying human embryogenesis. Furthermore, adherent cultures do not reflect the complexities and interactions that emerge in three dimensional structures. Increasingly, other primates are being studied and used as referenced but this does not remove the ethical issues that are associated with this kind of study.Over the last few years we have established an experimental system based on mouse ESCs which, surprisingly, reproduces to a very high degree the early stages of embryonic development and patterning, most notably, the process of gastrulation. The structures mirror the embryo until, approximately, stage 10 (almost half way through its development). An important feature of these organoids, that we call 'gastruloids' because of their ability to imitate gastrulation, is that they develop in the absence of the extraembryonic tissues that mediate the interactions between the embryo and the mother. A second feature is that they lack a head and brain and consist,only, of structures from the neck down. Here we propose to build on these observations and preliminary results that we have obtained to establish a similar system for human ESCs. This will allow an unprecedented access to the mechanisms underlying the early stages of human development and, in particular, the cellular and molecular processes that underlie the establishment of primordial for tissues and organs. Furthermore, the lack of a brain and a head and importantly, the inability of these organoids to interact with the mother account for many of the ethical considerations that apply to embryos.

可以在体外哄骗小鼠和人类胚胎干细胞（ESC）形成组织和器官的发现提高了人们的期望，即相关的培养指导分化方案将为成功发展有理性再生医学提供基础。但是现在是早期。目前，最成功的实验是通过鼠标ESC进行的，因为它们允许在知名和标准化的系统中进行广泛的实验。同样，尽管有一些协议可以产生器官，例如结构的器官 - 体外，但协议既不强大，也不足够可重现，以至于没有太多使用。这样做的原因是，尽管我们在理解控制特定细胞类型的基因方面取得了重大进步，但我们对这些基因的表达如何转化为表征组织和器官的三维结构几乎没有理解。了解这需要一个用户友好的三维实验系统，该系统模仿胚胎。在人类组织和器官的情况下，这种情况甚至更具挑战性，因为在这种情况下，我们对人类胚胎的发展和对它们的细胞和分子基础的知识几乎没有深入的了解。在这一重要的研究领域取得进展也受到与人类胚胎使用相关的明显道德问题和法规的限制。 ESC提供了一种替代性实验系统，但是当前对人类ESC的研究将自己限制在依从性文化中，或者使用小鼠和小鼠ESC作为人类生物学的标准参考，因为它在基本的发展过程中具有肤浅的相似性。但是，这两种物种之间存在显着差异，这些物种详细考虑，强调需要更好地理解人类胚胎发生的特定细胞和分子特征。此外，粘附文化不能反映三维结构中出现的复杂性和相互作用。越来越多的其他灵长类动物正在被研究和使用，但这并不能消除与此类研究相关的道德问题。在过去的几年中，我们建立了一个基于小鼠ESC的实验系统，令人惊讶的是，该系统将重现为非常高度的胚胎发育和图案的早期阶段，最值得注意的是胃肠道。该结构反映了胚胎，直到大约是第10阶段（几乎通过其发育中的一半）。这些器官的一个重要特征是，我们称其为“胃类动物”，因为它们模仿了胃胃，它们在没有介导胚胎与母亲之间相互作用的超胚的组织的情况下发展。第二个特征是它们缺乏头脑和大脑，并且仅由颈部向下的结构组成。在这里，我们建议以这些观察结果和初步结果为基础，以建立人类ESC的类似系统。这将允许对人类发育早期阶段的基础机制，尤其是细胞和分子过程，这些机制是基于组织和器官建立原始的细胞和分子过程。此外，缺乏大脑和头部，重要的是，这些类器官与母亲相互作用的无法说明适用于胚胎的许多道德考虑因素。