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Quantitative analysis of human notochord development

Reference	BB/W002310/1
Principal Investigator / Supervisor	Dr Guillaume Blin
Co-Investigators / Co-Supervisors
Institution	University of Edinburgh
Department	Sch of Biological Sciences
Funding type	Research
Value (£)	696,806
Status	Current
Type	Research Grant
Start date	01/02/2022
End date	31/01/2025
Duration	36 months

Abstract

Notochord progenitors (NotoPs) are vital for embryonic development and are the precursors of the cells responsible for intervertebral discs homeostasis. Unlike any other connective tissues, intervertebral discs start ageingearly in life, during childhood. This ageing process is the prevalent cause of chronic low back pain and a major cause of disability. There is no doubt that an unlimited access to NotoPs would open numerous opportunities for basic and translational biomedical applications. 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 protocols 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 tractable system is the first to use micropatterning technology 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 topology and signalling dynamics interplay 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).

Summary

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).

Committee	Research Committee C (Genes, development and STEM approaches to biology)
Research Topics	X – not assigned to a current Research Topic
Research Priority	X – Research Priority information not available
Research Initiative	X - not in an Initiative
Funding Scheme	X – not Funded via a specific Funding Scheme

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