Quantitative analysis of human notochord development

人类脊索发育的定量分析

• 批准号: BB/W002310/1
• 负责人: Guillaume Blin
• 金额: $ 88.79万
• 依托单位: University of Edinburgh
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FW002310%2F1
• 关键词: Quantitative; analysis; human; notochord; development

Notochord progenitors (NotoPs) are vital for embryonic development and are the precursors of the cells that form and maintain intervertebral discs. Unlike any other connective tissues, intervertebral discs start ageing early in life during childhood. This ageing process is the prevalent cause of chronic low back pain impacting the quality of life in more than 50% of the global population and a major cause of mobility limitations. There is no doubt that an unlimited access to NotoPs would open numerous opportunities for basic biomedical research and regenerative medicine. However, NotoPs cannot be obtained from healthy individuals and it is currently not possible to reliably obtain NotoPs from the differentiation of embryonic stem cells (ESCs). This is because current strategies have been devised on the basis of an incomplete, qualitative-only understanding of early notochord development.To tackle this challenge and circumvent the technical and ethical limitations inherent to research on rare embryonic cell populations, we have developed an innovative experimental system termed hAXIOMs. This novel tractable in vitro system uses micropatterning, a technology which enables us to guide the development of human ESCs into standardised patterns of notochord and all the lineages that surround the emergence of NotoPs.Here, we propose to use hAXIOMs together with quantitative methods developed in our lab to establish how tissue organisation and mechanics interplay with signalling dynamics to define NotoPs. We will leverage this new knowledge to produce a robust protocol for the efficient derivation of NotoPs from hESCs.This project will a) enable the use of NotoPs for regenerative medicine and basic biomedical research, b) inform our understanding and control over other therapeutically relevant cell types that emerge in the immediate vicinity of NotoPs and c) establish hAXIOMs as a paradigm experimental system allowing us in the future to investigate healthy axial development and the embryonic origins of scoliosis (one of the causes of severe intervertebral disc degeneration).

脊索祖细胞（NotoPs）对胚胎发育至关重要，是形成和维持椎间盘的细胞的前体。与任何其他结缔组织不同，椎间盘在童年时期就开始老化。这种老化过程是慢性腰痛的普遍原因，影响全球50%以上人口的生活质量，也是活动受限的主要原因。毫无疑问，无限制地使用NotoPs将为基础生物医学研究和再生医学提供许多机会。然而，NotoPs不能从健康个体获得，并且目前不可能从胚胎干细胞（ESC）的分化中可靠地获得NotoPs。这是因为目前的策略是基于对早期脊索发育的不完整的、仅定性的理解而设计的。为了应对这一挑战并规避对稀有胚胎细胞群研究所固有的技术和伦理限制，我们开发了一种称为hAXIOMs的创新实验系统。这种新的易处理的体外系统使用micropatterning，一种技术，使我们能够引导人类胚胎干细胞的发展成为标准化的模式脊索和所有的谱系，围绕出现NotoPs.在这里，我们建议使用hAXIOMs连同定量方法在我们的实验室开发，以建立组织组织和力学相互作用的信号动力学，以定义NotoPs。我们将利用这一新的知识，以产生一个强大的协议，从hESC的NotoPs的有效衍生。该项目将a）使NotoPs用于再生医学和基础生物医学研究，B）告知我们对在NotoPs附近出现的其他治疗相关细胞类型的理解和控制，以及建立hAXIOMs作为一个范例实验系统，使我们能够在未来研究健康的轴向发育和脊柱侧凸的胚胎起源（严重椎间盘退变的原因之一）。