Quantitative analysis of human notochord development
Lead Research Organisation:
University of Edinburgh
Department Name: Sch of Biological Sciences
Abstract
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).
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).
Technical Summary
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).
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).
Organisations
Publications
Malaguti M
(2024)
Enabling neighbour labelling: using synthetic biology to explore how cells influence their neighbours.
in Development (Cambridge, England)
Robles-Garcia M
(2024)
In vitro modelling of anterior primitive streak patterning with human pluripotent stem cells identifies the path to notochord progenitors
in Development
| Description | The mechanisms that define how our cells acquire their identity during development remain incompletely understood. In this work, our team has focused on an important population of cells called the notochord which emerges at the end of week 2 of human development. Although transient, the notochord plays an important role during embryogenesis, both as a structure that ensures the mechanical integrity of the embryo and as a source of signals that coordinate the development of surrounding tissues. Later on, notochord cells give rise to the cellular region responsible for maintaining intervertebral discs. Before our work, the mechanisms defining the notochord lineage early during development were unclear. We have shown that the temporal sequence and the duration of the signals received by the cells play a critical role in the definition of notochord cells. By manipulating these signals, we can now efficiently generate notochord cells in culture to further study this lineage. Derivation of specific cell types often leads to heterogeneous cell populations. We have uncovered one reason explaining why this heterogeneity emerges. Our work will also be useful to our colleagues wishing to improve the derivation efficiency of other clinically relevant lineages. In addition to the scientific discovery described above, several master and undergraduate students, two technicians, one PhD student and one postdoc were trained in cutting-edge techniques of in vitro modelling of human development. |
| Exploitation Route | Our results will be useful to rationalise efficient protocols for deriving clinically relevant human notochord cells. We envisage that clinical trials for the regeneration of injured intervertebral discs will be possible when it is possible to produce and maintain human notochord cells at scale. |
| Sectors | Education Healthcare Pharmaceuticals and Medical Biotechnology |
| URL | https://doi.org/10.1242/dev.202983 |
| Title | Robles-Garcia et al. Development 2024 |
| Description | ## Access ## This dataset is held in the Edinburgh DataVault, directly accessible only to authorised University of Edinburgh staff. External users may request access to a copy of the data by contacting the Principal Investigator, Contact Person or Data Manager named on this page. University of Edinburgh users who wish to have direct access should consult the information about retrieving data from the DataVault at: https://www.ed.ac.uk/is/research-support/datavault. |
| Type Of Material | Database/Collection of data |
| Year Produced | 2024 |
| Provided To Others? | Yes |
| Impact | This dataset has only been published recently and we are not aware of a notable impact at the date of this submission. |
| URL | https://www.research.ed.ac.uk/en/datasets/ab11faab-c645-4e31-ac49-dc41532c85c2 |