14 NSFBIO: Asymmetric division and the temporal dynamics of cell motility
Lead Research Organisation:
University of Manchester
Department Name: School of Medical Sciences
Abstract
This project aims to define the fundamental mechanisms controlling cell migration during organ development. In growing tissues, cells usually replicate by symmetric division (or mitosis) to produce two identical daughter cells. But in some instances cell divisions are asymmetric and give rise to intrinsically distinct daughters. Asymmetric divisions play important roles in differential cell fate decisions, but have never previously been implicated in generating daughters with distinct motilities. This project will explore the molecular and cellular basis of post-mitotic asymmetry in cell motility and define the functional role of asymmetric divisions in the control of cell migration during tissue growth. In particular this work will evaluate how asymmetries is daughter cell signaling, shape and stiffness can profoundly affect cell motility following division. Not only will this research generate freely available novel computational methods and analysis tools suitable for a wide array of applications, the findings of this work will have wide-reaching implications for understanding the control of cell migration across a plethora of cellular systems and organisms. The project will additionally expose undergraduate and high school students (with emphasis on recruiting underrepresented groups) to integrated cross-disciplinary computational / experimental scientific approaches and provide hands-on experience of international collaborative research techniques upon the creation of several new, targeted, interactive Global Interface Science (GIS) workshops. Moreover, guidance on implementing similar GIS workshops anywhere worldwide will be widely disseminated via online media.
Technical Summary
Asymmetric cell division (ACD) specifies differential daughter cell fates in many systems, but has never before been implicated in determining the temporal dynamics of cell motility. This project will define how ACD acts as a novel symmetry-breaking mechanism to ensure daughter cells acquire distinct motilities during tissue growth. An integrated in silico and in vivo approach will be taken, innovating a novel multiscale hybrid, spatiotemporal agent-based model (ABM) that will inform single-cell live imaging experiments of endothelial cells in zebrafish embryos. These studies will probe ACD in motile cells, validate model predictions and altogether elucidate a previously unexplored role for mitosis in the control of migration. In particular, the interplay of ACD with cell signaling, geometry and mechanical motility cues across different scales, from the molecular to the cellular will be investigated through the following tasks: A) develop new modeling methodologies to investigate the role of localized intracellular dynamics in the establishment of asymmetric post-mitotic motility and functionally validate model predictions at sub-cellular resolution in vivo; B) Predict the effects of ACD-driven differences in cell architecture on motility dynamics in silico alongside quantification of dynamic alterations in cell architecture occurring during division in vivo; C) quantify pre- and post-mitotic fluctuations in cell tension at single-cell resolution in vivo and define the interplay of cell tension with the induction of ACD and differential motility in silico and in vivo. The products of this research will include novel computational ABM models and image analysis software, which will uniquely enable studies of key aspects of cell migration and will be made freely available to the wider scientific community.
Planned Impact
This project will produce societal impacts by:
1) providing new computational methods and image analysis software, made freely available via the PI's websites for the benefit of the
wider scientific community
2) international workshops will be organized to disseminate research outcomes and provide a platform for promoting integrated in silico/in vivo approaches
3) a broad range of populations, ranging from high school and undergraduate students to faculty, will experience unique training that will promote and cultivate cross-disciplinary, international collaborative research. Specific efforts will be made to attract underrepresented groups in science and engineering (STEM) subjects
4) The materials for implementing educational workshops will be widely disseminated via online media for other interested institutes to implement all over the world
1) providing new computational methods and image analysis software, made freely available via the PI's websites for the benefit of the
wider scientific community
2) international workshops will be organized to disseminate research outcomes and provide a platform for promoting integrated in silico/in vivo approaches
3) a broad range of populations, ranging from high school and undergraduate students to faculty, will experience unique training that will promote and cultivate cross-disciplinary, international collaborative research. Specific efforts will be made to attract underrepresented groups in science and engineering (STEM) subjects
4) The materials for implementing educational workshops will be widely disseminated via online media for other interested institutes to implement all over the world
People |
ORCID iD |
Shane Herbert (Principal Investigator) |
Publications
Costa G
(2017)
Endothelial cells divide unequally to sprout fairly.
in Cell cycle (Georgetown, Tex.)
Costa G
(2016)
Asymmetric division coordinates collective cell migration in angiogenesis.
in Nature cell biology
Page DJ
(2019)
Positive Feedback Defines the Timing, Magnitude, and Robustness of Angiogenesis.
in Cell reports
Sacilotto N
(2016)
MEF2 transcription factors are key regulators of sprouting angiogenesis.
in Genes & development
Description | The key aim of this grant was to determine what mechanisms regulate the asymmetric division of endothelial cells that regulates new blood vessel formation by angiogenesis. Using live cell imaging techniques during the development of zebrafish and computational models of this process we identified a mechanism that allows the simultaneous asymmetric division and migration of endothelial cells during new blood vessel formation. We found that asymmetric positioning of the mitotic spindle machinery generates daughters of distinct size that then go on to have distinct behaviours. As such, asymmetric division ensures that the leading and trailing hierarchy of cells that coordinates angiogenesis is maintained in the fate of proliferative tissue growth. This is the first time that asymmetric division has been implicated in driving the dynamic morphogenesis of a tissue and suggests that similar mechanisms may control the collective movement of other tissues - such as metastasising tumour cells in cancer. The results of this work were recently published in Nature cell biology (Impact factor 19; DOI: 10.1038/ncb3443). In the process of generating this data we developed an in silico computation model - in collaboration with Kate Bentley, Harvard University - of the cell behaviours that regulate new blood vessels formation that can be used as a test bed for predictive interrogation of the mechanisms that regulate angiogenesis. |
Exploitation Route | We have presented these findings at multiple international conferences and so far published a high impact paper on these studies in Nature Cell Biology (Impact factor 19). |
Sectors | Pharmaceuticals and Medical Biotechnology,Other |
URL | http://www.nature.com/ncb/journal/v18/n12/full/ncb3443.html |
Description | Deciphering morphogenetic cues encoded in cell shape |
Amount | £1,740,984 (GBP) |
Funding ID | 219500/Z/19/Z |
Organisation | Wellcome Trust |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 03/2020 |
End | 04/2025 |
Description | Spatiotemporal control of endothelial tip/stalk cell identity and angoigenesis |
Amount | £234,470 (GBP) |
Organisation | British Heart Foundation (BHF) |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 03/2016 |
End | 03/2019 |
Description | Wellcome Trust Sir Henry Wellcome Fellowship |
Amount | £250,000 (GBP) |
Funding ID | 206492/Z/17/Z |
Organisation | Wellcome Trust |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 08/2017 |
End | 08/2021 |
Title | Computational modelling of blood vessel sprouting |
Description | We generated a in silico model of blood vessel morphogenesis that mimics the behaviours of cells observed in vivo during zebrafish development. As such this tool can be used as a computational test bed to investigate the mechanisms of blood vessel formation. |
Type Of Material | Model of mechanisms or symptoms - non-mammalian in vivo |
Provided To Others? | No |
Impact | This model contributed to our recent publication in Nature Cell Biology: Costa G, Page DJ, Harrington, K, Bentley, K, Herbert, SP. Asymmetric Division Coordinates Collective Cell Migration in Angiogenesis. (2016) Nature Cell Biology. 18(12), 1292-1301 Moreover, this model was instrumental to our recently funded grant with the British Heart Foundation: "Spatiotemporal control of endothelial tip/stalk cell identity and angoigenesis" £234,470. |
Title | Computational modelling of blood vessel sprouting |
Description | We generated a in silico model of blood vessel morphogenesis that mimics the behaviours of cells observed in vivo during zebrafish development. As such this tool can be used as a computational test bed to investigate the mechanisms of blood vessel formation |
Type Of Material | Computer model/algorithm |
Provided To Others? | No |
Impact | This model contributed to our recent publication in Nature Cell Biology: Costa G, Page DJ, Harrington, K, Bentley, K, Herbert, SP. Asymmetric Division Coordinates Collective Cell Migration in Angiogenesis. (2016) Nature Cell Biology. 18(12), 1292-1301 Moreover, this model was instrumental to our recently funded grant with the British Heart Foundation: "Spatiotemporal control of endothelial tip/stalk cell identity and angoigenesis" £234,470. |
Description | Computational modelling of angiogenesis |
Organisation | Beth Israel Deaconess Medical Center |
Department | Centre for Vascular Biology Research |
Country | United States |
Sector | Academic/University |
PI Contribution | Access to our data on the behaviour of endothelial cells during angiogenesis in vivo and intellectual input to a collaborative project that sought to computationally model these behaviours in silico - in collaboration with the lab of Katie Bentley. |
Collaborator Contribution | Katie Bentley's group developed a computational model of endothelial cell behaviour during angiogenesis during angiogenesis that was critical to generative predictive hypotheses regarding the molecular and cellular control of this process |
Impact | Multidisciplinary collaboration: Computation modelling and Developmental/cell biology. Key outputs: Manuscript published in Nature Cell Biology (Impact factor 19) Costa G, Page DJ, Harrington, K, Bentley, K, Herbert, SP. Asymmetric Division Coordinates Collective Cell Migration in Angiogenesis. (2016) Nature Cell Biology. 18(12), 1292-1301 |
Start Year | 2015 |
Description | Article in the Biological Sciences Review magazine |
Form Of Engagement Activity | A magazine, newsletter or online publication |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Schools |
Results and Impact | I prepared an article on new blood vessel formation for the Biological Sciences Review - a magazine distributed to schools with in the UK as a resource for all students and teachers of the biological sciences. In particular the magazine is aimed at informing A-level students about various research topics that are relevant to their studies and bridges the gap between their textbooks and published research. |
Year(s) Of Engagement Activity | 2016 |
URL | https://www.hoddereducation.co.uk/Product/9781471856648 |
Description | Teacher's summer school |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Schools |
Results and Impact | Participated in a workshop for teachers from local schools to learn about the science conducted at the university and generate ideas for how they could integrate this information into their teaching activities. In particular I informed the audience of how the zebrafish model can be used in biological studies. |
Year(s) Of Engagement Activity | 2015 |
URL | http://www.supi.manchester.ac.uk/events/flssummerschool/ |