Pathways governing the competitive behaviour of pluripotent cells
Lead Research Organisation:
Imperial College London
Department Name: National Heart and Lung Institute
Abstract
AE1: Signal transduction pathways regulating stem cell fitness/behaviour in the early mouse embryo AE2: ES cell biology
Technical Summary
Ensuring that mutations are not propagated within stem cell populations is key to proper development and homeostasis. This is especially relevant when it comes to pluripotent cells, that not only can give rise to all lineages, including the germ line, but that are also of great importance to regenerative medicine. We have found that cell competition is a novel mechanism that ensures the fitness of the mammalian pluripotent stem cell pool. We found that during the onset of differentiation, cell competition measures the relative fitness of pluripotent cells and eliminates those cells that are less-fit than their neighbours. This implies that cell fitness is not only a cell-intrinsic property, but is also measured relative to a cells' neighbours. We do not know how cells perform this relative fitness sensing and this will be the thrust of this proposal. In preliminary work to this proposal we have identified that specifically when wild-type and defective pluripotent cells are confronted with each other at the onset of differentiation, the defective cells decrease mTOR signalling and this decrease is sufficient to explain their elimination. Furthermore, we have shown that restoring mTOR signalling in loser cells is sufficient to rescue their elimination. These results indicate that the mTOR pathway is key read-out of the competitive behaviour of cells. Here we will do four things. First, we will study the pathways regulated by mTOR during differentiation to understand how mTOR mediates defective cell elimination. We will also study the signals upstream of mTOR to gain insight into the mechanisms by which cells communicate their relative fitness levels. Third, we will screen for novel pathways that regulate cell competition. Finally, we will study what happens when cell competition fails to gain insight into the fate of cells not eliminated by this mechanism.
Planned Impact
Our studies will uncover the mechanisms that ensure the fitness of pluripotent stem cells. The large promise that pluripotent stem cells hold for regenerative medicine, where stem cell are induced to differentiate towards specialised cells that are then transplanted into patients, has carried with it a large degree of interest both from the academic and medical communities. Furthermore, with the advances in reprogramming there is an enormous scope for applying in vitro differentiation of patient-derived induced pluripotent stem (iPS) cells to study diseases. However, increased knowledge about how specific cell types are induced in an irreversible way as well as how to differentiate cells down specific lineages is vital to control that the correct cell types are generated before these stem cell therapy becomes meaningful clinically. Therefore, the results obtained in this study will be of direct relevance to translational research. Given that understanding how cellular fitness is regulated is a key question in cancer, our work will also be of interest to researchers working in this field.
The primary beneficiaries and users of this research are members of the academic sector - research workers, teachers and students. Other beneficiaries are the general public and commercial sector. In particular, the data obtained in this project will benefit the companies developing stem cell-based assays for drug screening (e.g. AstraZeneca) as well as companies developing media for pluripotent stem cell maintenance and differentiation (e.g. STEMCELL Technologies, Millipore), and pharmaceutical and biotech companies developing hESC-based cell replacement therapies for treatment of degenerative diseases (e.g. Advanced Cell Technologies, Viacyte).
A further beneficiary of our work will be the lay public. Given the medical relevance and ethical implications of understanding developmental processes, and its impact on stem cell biology, our work will provide factual input to and therefore benefit the public discussion about the advantages and risks of stem cell therapy.
The results of this research will be conveyed to other researchers through the publication of findings in peer-reviewed journals, by reporting unpublished work at conferences and through personal communication with other scientists. Though the results will primarily be disseminated through scientific journals, we will liaise with dedicated Media Teams at Imperial College and the University of Sheffield to issue a press release when appropriate. We take seriously the responsibility of scientists to engage with the lay public, to raise awareness among them of the results of publicly funded research, to openly debate ethical issues relating to our research so that public opinion may be formed in an informed manner and to take the excitement of our research to the children of today, who will be the scientists of tomorrow. For these reasons we engage through the University but also as individuals in activities aimed at the public dissemination of science.
This project will also train early-career researchers in emerging methodologies, contributing to their career development, as well as producing individuals capable of carrying out future research in the biomedical sciences. At a time when industry is moving in the direction of interdisciplinary research, such individuals will be highly sought-after not only in academia but also in the commercial sector.
The primary beneficiaries and users of this research are members of the academic sector - research workers, teachers and students. Other beneficiaries are the general public and commercial sector. In particular, the data obtained in this project will benefit the companies developing stem cell-based assays for drug screening (e.g. AstraZeneca) as well as companies developing media for pluripotent stem cell maintenance and differentiation (e.g. STEMCELL Technologies, Millipore), and pharmaceutical and biotech companies developing hESC-based cell replacement therapies for treatment of degenerative diseases (e.g. Advanced Cell Technologies, Viacyte).
A further beneficiary of our work will be the lay public. Given the medical relevance and ethical implications of understanding developmental processes, and its impact on stem cell biology, our work will provide factual input to and therefore benefit the public discussion about the advantages and risks of stem cell therapy.
The results of this research will be conveyed to other researchers through the publication of findings in peer-reviewed journals, by reporting unpublished work at conferences and through personal communication with other scientists. Though the results will primarily be disseminated through scientific journals, we will liaise with dedicated Media Teams at Imperial College and the University of Sheffield to issue a press release when appropriate. We take seriously the responsibility of scientists to engage with the lay public, to raise awareness among them of the results of publicly funded research, to openly debate ethical issues relating to our research so that public opinion may be formed in an informed manner and to take the excitement of our research to the children of today, who will be the scientists of tomorrow. For these reasons we engage through the University but also as individuals in activities aimed at the public dissemination of science.
This project will also train early-career researchers in emerging methodologies, contributing to their career development, as well as producing individuals capable of carrying out future research in the biomedical sciences. At a time when industry is moving in the direction of interdisciplinary research, such individuals will be highly sought-after not only in academia but also in the commercial sector.
Organisations
- Imperial College London (Lead Research Organisation)
- Francis Crick Institute (Collaboration)
- UNIVERSITY OF OXFORD (Collaboration)
- University College London (Collaboration)
- University of Lisbon (Collaboration)
- Osaka University (Collaboration)
- National Institutes of Health (NIH) (Collaboration)
- Medical Research Council (MRC) (Collaboration)
- IMPERIAL COLLEGE LONDON (Collaboration)
- Spanish National Centre for Cardiovascular Research (Collaboration)
People |
ORCID iD |
Tristan Rodriguez (Principal Investigator) |
Publications
Lawlor K
(2020)
Transcriptional versus metabolic control of cell fitness during cell competition.
in Seminars in cancer biology
Lima A
(2021)
Cell competition acts as a purifying selection to eliminate cells with mitochondrial defects during early mouse development
in Nature Metabolism
Bowling S
(2018)
P53 and mTOR signalling determine fitness selection through cell competition during early mouse embryonic development.
in Nature communications
Roman-Trufero M
(2020)
Evolution of an Amniote-Specific Mechanism for Modulating Ubiquitin Signaling via Phosphoregulation of the E2 Enzyme UBE2D3.
in Molecular biology and evolution
Lawlor K
(2020)
Glioblastoma stem cells induce quiescence in surrounding neural stem cells via Notch signaling.
in Genes & development
Price CJ
(2021)
Genetically variant human pluripotent stem cells selectively eliminate wild-type counterparts through YAP-mediated cell competition.
in Developmental cell
Pernaute B
(2022)
DRP1 levels determine the apoptotic threshold during embryonic differentiation through a mitophagy-dependent mechanism.
in Developmental cell
Bowling S
(2019)
Cell competition: the winners and losers of fitness selection.
in Development (Cambridge, England)
Lima A
(2018)
The Mitochondria and the Regulation of Cell Fitness During Early Mammalian Development.
in Current topics in developmental biology
Lima A
(2021)
Cell Competition: A Choreographed Dance of Death.
in Current biology : CB
Description | Marie Curie Actions: - Marie Curie Fellowship |
Amount | £122,303 (GBP) |
Funding ID | 709010 |
Organisation | European Union |
Sector | Public |
Country | European Union (EU) |
Start | 01/2017 |
End | 12/2019 |
Description | Rosetree pilot grant |
Amount | £20,000 (GBP) |
Organisation | Rosetrees Trust |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 06/2017 |
End | 07/2019 |
Description | External Collaborators |
Organisation | National Institutes of Health (NIH) |
Country | United States |
Sector | Public |
PI Contribution | Exchange of ideas, reagents and joint publications |
Collaborator Contribution | Exchange of ideas, reagents and joint publicationsExchange of ideas, reagents and joint publicationsExchange of ideas, reagents and joint publicationsExchange of ideas, reagents and joint publicationsExchange of ideas, reagents and joint publicationsExchange of ideas, reagents and joint publicationsExchange of ideas, reagents and joint publications |
Impact | Joint publications |
Description | External Collaborators |
Organisation | Osaka University |
Country | Japan |
Sector | Academic/University |
PI Contribution | Exchange of ideas, reagents and joint publications |
Collaborator Contribution | Exchange of ideas, reagents and joint publicationsExchange of ideas, reagents and joint publicationsExchange of ideas, reagents and joint publicationsExchange of ideas, reagents and joint publicationsExchange of ideas, reagents and joint publicationsExchange of ideas, reagents and joint publicationsExchange of ideas, reagents and joint publications |
Impact | Joint publications |
Description | External Collaborators |
Organisation | Spanish National Centre for Cardiovascular Research |
Country | Spain |
Sector | Public |
PI Contribution | Exchange of ideas, reagents and joint publications |
Collaborator Contribution | Exchange of ideas, reagents and joint publicationsExchange of ideas, reagents and joint publicationsExchange of ideas, reagents and joint publicationsExchange of ideas, reagents and joint publicationsExchange of ideas, reagents and joint publicationsExchange of ideas, reagents and joint publicationsExchange of ideas, reagents and joint publications |
Impact | Joint publications |
Description | External Collaborators |
Organisation | University College London |
Department | Biosciences |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Exchange of ideas, reagents and joint publications |
Collaborator Contribution | Exchange of ideas, reagents and joint publicationsExchange of ideas, reagents and joint publicationsExchange of ideas, reagents and joint publicationsExchange of ideas, reagents and joint publicationsExchange of ideas, reagents and joint publicationsExchange of ideas, reagents and joint publicationsExchange of ideas, reagents and joint publications |
Impact | Joint publications |
Description | External Collaborators |
Organisation | University of Lisbon |
Department | Institute for Molecular Medicine |
Country | Portugal |
Sector | Academic/University |
PI Contribution | Exchange of ideas, reagents and joint publications |
Collaborator Contribution | Exchange of ideas, reagents and joint publicationsExchange of ideas, reagents and joint publicationsExchange of ideas, reagents and joint publicationsExchange of ideas, reagents and joint publicationsExchange of ideas, reagents and joint publicationsExchange of ideas, reagents and joint publicationsExchange of ideas, reagents and joint publications |
Impact | Joint publications |
Description | External Collaborators |
Organisation | University of Oxford |
Department | Department of Biochemistry |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Exchange of ideas, reagents and joint publications |
Collaborator Contribution | Exchange of ideas, reagents and joint publicationsExchange of ideas, reagents and joint publicationsExchange of ideas, reagents and joint publicationsExchange of ideas, reagents and joint publicationsExchange of ideas, reagents and joint publicationsExchange of ideas, reagents and joint publicationsExchange of ideas, reagents and joint publications |
Impact | Joint publications |
Description | External Collaborators |
Organisation | University of Oxford |
Department | Department of Physiology, Anatomy and Genetics |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Exchange of ideas, reagents and joint publications |
Collaborator Contribution | Exchange of ideas, reagents and joint publicationsExchange of ideas, reagents and joint publicationsExchange of ideas, reagents and joint publicationsExchange of ideas, reagents and joint publicationsExchange of ideas, reagents and joint publicationsExchange of ideas, reagents and joint publicationsExchange of ideas, reagents and joint publications |
Impact | Joint publications |
Description | Internal collaborator Imperial College - GCK |
Organisation | Imperial College London |
Department | Department of Medicine |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Intellectual and data generation |
Collaborator Contribution | Intellectual and providing mouse lines |
Impact | Generation of mouse lines with mosaic Glucokinase deletion |
Start Year | 2017 |
Description | Internal collaborator MRC LMS |
Organisation | Medical Research Council (MRC) |
Department | MRC Clinical Sciences Centre (CSC) |
Country | United Kingdom |
Sector | Public |
PI Contribution | Intellectual and data generation |
Collaborator Contribution | Intellectual contribution and deep mRNA-sequencing |
Impact | Paper in revision |
Start Year | 2014 |
Description | Metabolic analysis |
Organisation | Francis Crick Institute |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | We have provided wild-type and mutant cell lines for the study |
Collaborator Contribution | The collaborator helped us with metabolic analysis. |
Impact | The main output is the metabolic analysis of wild-type and mutant cell lines. |
Start Year | 2023 |