Cell-matrix biology of the vascular progenitor cell niche.

Lead Research Organisation: University of Manchester
Department Name: Life Sciences

Abstract

Diseases of the heart and blood vessels are one of the major causes of illness and death in Western society, and they represent a huge healthcare burden. This proposal is characterise a particular type of immature tissue repair cell, termed mesenchymal progenitor cell (or ?MPC?), and then exploit them to repair damaged hearts and regenerate blood vessels. Not only do MPCs have great therapeutic potential, but they can be expanded and analysed in the laboratory. Although clinical trials of transplanted MPCs into damaged hearts have been encouraging, limited understanding of their underlying biology remains a major obstacle to realising their therapeutic potential. Our timely proposal is to define their ?molecular signatures? and generate a comprehensive (open access) database of MPC marker molecules, determine how they regulate cell fate, and test how MPCs repair damaged blood vessels and injured hearts.

Technical Summary

This proposal is to define the cell-extracellular matrix biology of the vascular mesenchymal progenitor cell (MPC) niche, as a basis for developing effective new cardiovascular therapies. MPCs offer immense opportunities for treating cardiovascular disease, given their accessibility, immunosuppressive and anti-inflammatory properties, paracrine contributions to tissue repair and potential to differentiate along vascular lineages. However, their underlying biology remains poorly defined and a major obstacle to realising their therapeutic potential. Signals across the cell-matrix interface control numerous aspects of cell biology, including survival, proliferation, migration and differentiation. This timely interdisciplinary proposal is to exploit our combined unique international strengths in cell-matrix and mesenchymal progenitor cell biology, state-of-the-art proteomics and glycomics, and in vivo models to define the MPC cell-matrix niche and apply this knowledge therapeutically. We will undertake systematic analysis to define the cell-matrix niche of MPCs from bone marrow and umbilical cord, generating a comprehensive (open access) database. This knowledge will allow us to determine how cell-matrix niche molecules control MPC fate decisions, to select MPCs reproducibly and track them during vascular regeneration in vivo, and to exploit the niche to enhance MPC-mediated repair of damaged blood vessels in injured hearts and the performance of engineered vascular grafts. Our studies will underpin a future pipeline of interlinked basic and translational studies of lead target proteins as determinants of cell fate and MPC-based cardiovascular therapies. The ultimate goal is to direct revascularisation of ischaemic heart and peripheral tissues. Thus, we offer a timely and exceptional opportunity to advance novel progenitor cell therapies for cardiovascular repair.

Publications

10 25 50

 
Description BBSRC CASE Studentship
Amount £50,000 (GBP)
Organisation Johnson & Johnson 
Sector Private
Country United States
Start 10/2011 
End 09/2014
 
Description British Heart Foundation PhD studentship
Amount £100,000 (GBP)
Organisation British Heart Foundation (BHF) 
Sector Charity/Non Profit
Country United Kingdom
Start 09/2014 
End 08/2017
 
Description EPSRC-MRC Centre for Doctoral Training in Regenerative Medicine
Amount £4,500,000 (GBP)
Funding ID Not yet known 
Organisation Engineering and Physical Sciences Research Council (EPSRC) 
Sector Academic/University
Country United Kingdom
Start 04/2014 
End 09/2022
 
Description EPSRC-MRC Centre for Doctoral Training in Regenerative Medicine (capital supplement)
Amount £288,296 (GBP)
Organisation Engineering and Physical Sciences Research Council (EPSRC) 
Sector Academic/University
Country United Kingdom
Start 01/2015 
 
Description The Leverhulme Trust Visiting Professorship
Amount £18,720 (GBP)
Funding ID VP-2016-014 
Organisation The Leverhulme Trust 
Sector Academic/University
Country United Kingdom
Start 02/2017 
End 07/2017
 
Description UK Regenerative Medicine Platform (niche hub phase 2 supplement)
Amount £150,000 (GBP)
Organisation UK Regenerative Medicine Platform 
Sector Academic/University
Country United Kingdom
Start 12/2014 
End 11/2016
 
Description UK Regenerative Platform Hub
Amount £400,000 (GBP)
Organisation UK Regenerative Medicine Platform 
Sector Academic/University
Country United Kingdom
Start 11/2013 
End 10/2017
 
Description UKRMP Capital Funding call (2013)
Amount £672,000 (GBP)
Organisation UK Regenerative Medicine Platform 
Sector Academic/University
Country United Kingdom
Start 10/2013 
End 03/2014
 
Title Quantitative proteomics of mesenchymal progenitor cell niche. 
Description We generated cell membrane-enriched preparations, from human mesenchymal stem cells (MSCs) and umbilical cord perivascular cells (HUCPVCs), and conducted quantitative proteomic analysis of their protein composition. The data are now being verified by qPCR and immunobiology, and initial functional studies have also begun. We anticipate that new markers for mesenchymal progenitor cells will emerge, and that this information will be published next year. 
Type Of Material Biological samples 
Provided To Others? No  
Impact None to date - data are still being analysed. 
 
Description Coyle 
Organisation University of Nottingham
Department Division of Child Health, Obstetrics and Gynaecology
Country United Kingdom 
Sector Hospitals 
PI Contribution In this collaboration I provide matrix biology expertise, stem cell biology expertise and materials science expertise to generate in vitro models of childrens' brain tumour.
Collaborator Contribution Dr Beth Coyle is a long-standing expert in childrens' brain tumour, investigating the mechanistic basis of initiation and spread of disease.
Impact The collaboration is multi-disciplinary linking cell biology, cancer biology and materials science. Together we are developing novel models of childrens' brain tumour.
Start Year 2017
 
Description Glycomics analysis (with P. Rudd) 
Organisation University College Dublin
Country Ireland 
Sector Academic/University 
PI Contribution Dr Cathy Merry established this collaboration with Professor Pauline Rudd in Dublin, who is a world-leader in N-glycan analysis and profiling. Dr Rebecca Holley, postdoc on this grant, prepared progenitor cell membrane samples and took them to Dublin for analysis and to learn the methodology (in order to establish it in Manchester).
Collaborator Contribution Professor Rudd provided support, lab reagents and training to Dr Holley, as outlined above.
Impact None yet, but manuscript in preparation (Dr Holley is about to go on maternity leave, so expected submission late 2013).
Start Year 2012
 
Description Internal (Manchester) collaborations for quantitative proteomics and glycomics analysis 
Organisation University of Manchester
Country United Kingdom 
Sector Academic/University 
PI Contribution My lab leads on the mesenchymal stem cell biology (culture, receptor/functional studies).
Collaborator Contribution All other PIs involved in project design. In particular, Ann Canfield (qProteomics, progenitor cell biology), Cathy Merry (Glycomics and qProteomics, progenitor cells), Tony Whetton (qProteomics).
Impact 1 paper in Stem Cells. 1-2 manuscripts in preparation with qProteomics and Glycomics data. We have completed the initial data collection for qProteomic analysis of the mesenchymal progenitor cell-matrix niche, and are currently validating a number of identified potential progenitor cell markers, as well as starting some functional assays. Glycomic studies are progressing well (led by Merry).
Start Year 2011
 
Description UK Regenerative Medicine Platform Hub (Stem Cell Niche) 
Organisation UK Regenerative Medicine Platform
Department Scottish Centre for Regenerative Medicine (lead), University of Edinburgh
Country United Kingdom 
Sector Academic/University 
PI Contribution UK Regenerative Medicine Platform Hub partner, 'Stem cell niche', led by Edinburgh.
Collaborator Contribution Partner on above hub. Proteomic and biochemical analysis of stem cell niches.
Impact Ongoing November 2014. New Phase 2 award to generate quality-controlled) extracelular matrix proteins (niche molecules) for UKRMP partners.
Start Year 2013
 
Description Whitelock 
Organisation The Leverhulme Trust
Country United Kingdom 
Sector Academic/University 
PI Contribution I am hosting a visit by Prof. John Whitelock. While working with our group John is learning how to carry out CRISPR modification of embryonic stem cell lines to model extracellular matrix related disease.
Collaborator Contribution While working with our group John is supporting multiple projects providing knowledge and reagents to investigate the extracellular matrix in natural and synthetic matrices.
Impact The collaboration is multi-disciplinary, covering cell biology, biochemistry and materials science. Outputs so far are primary increased knowledge and reagent development.
Start Year 2017
 
Description 'The heart as a pump', a public engagement activity held at MOSI as part of Manchester Science Fesitval, October 2016 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact This event was part of Manchester Science Festival. Its aim was to inform members of the general public about hearts and heart disease and the research conducted within the Institute of Cardiovascular Sciences at the University of Manchester. We run lots of different hands-on activities to demonstrate how the heart and blood vessels work and what goes wrong in disease. Some of the activities also highlight our current research. We always have lots of really good discussions with the general public and obtain fantastic feedback: 'I liked looking at arteries and seeing which one was healthy'; 'I liked crawling through the blood vessels'; 'It was sooooo hard crawling through the diseased vessel'; 'We enjoyed learning about stents and seeing how big different hearts were'; 'I liked dressing up as a scientist'; 'Learning what is good and bad for your heart'; 'Fascinating learning about stem cells'; 'I really want to be a scientist'.
Year(s) Of Engagement Activity 2016
 
Description - The Body Experience, Manchester Museum 2017 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact This is an annual event organised by the Faculty of Biology, Medicine and Health at the University of Manchester. I organise the heart and blood vessel activities for the event. We aim is to inform members of the general public about hearts and heart disease and the research conducted within the Institute of Cardiovascular Sciences at the University of Manchester. We run lots of different hands-on activities to demonstrate how the heart and blood vessels work and what goes wrong in disease. Some of the activities also highlight our current research. We always have lots of really good discussions with the general public and obtain fantastic feedback: 'I liked looking at arteries and seeing which one was healthy'; 'I liked crawling through the blood vessels'; 'It was sooooo hard crawling through the diseased vessel'; 'We enjoyed learning about stents and seeing how big different hearts were'; 'I liked dressing up as a scientist'; 'Learning what is good and bad for your heart'; 'Fascinating learning about stem cells'; 'I really want to be a scientist'.
Year(s) Of Engagement Activity 2017
 
Description Biological Sciences Review 
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 am the Medical Sciences Editor of Biological Sciences Review, which is a magazine aimed at 6th form Biology A level students. I have commissioned several articles for this magazine on heart and heart related topics; including one written by Dr Gareth Hyde (post-doc on this award) entitled 'Bone in blood vessels'. I also edit other articles for the magazine.

Approx 14,000 A-level students subscribe to this magazine annually.
Year(s) Of Engagement Activity 2010,2011,2012,2013,2014
 
Description Invited talk Gordon Research Conference 'Signalling by Adhesion Receptors' June 22-27 2014 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Research debate and collaborative links.

Scientific visibility.
Year(s) Of Engagement Activity 2014
 
Description Invited talk, Imperial College London; 11th November 2013 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach National
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact Invited talk at Imperial College London (mesenchymal stem cells); new research links.
Year(s) Of Engagement Activity 2013
 
Description Manchester Public Engagement 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Type Of Presentation Workshop Facilitator
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact Dr Ann Canfield has contributed to interactive displays on blood vessels, for the general public (Manchester Science Week 2011, Manchester Museum of Science and Industry 2012).

Public interest.
Year(s) Of Engagement Activity 2011,2012
 
Description Nuffield 6th form student projects (summer) 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? Yes
Geographic Reach Local
Primary Audience Schools
Results and Impact 2 students per summer (3-5 days in lab)

Students enjoy doing 'hands-on' science projects in our lab.
Year(s) Of Engagement Activity 2011,2012
 
Description School children visiting our Faculty 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Type Of Presentation Workshop Facilitator
Geographic Reach Local
Primary Audience Schools
Results and Impact My lab group contributed to explaining to school children visiting our faculty about our cell-matrix research, and some of our experimental approaches.

Students enjoyed the experience.
Year(s) Of Engagement Activity 2011
 
Description School visit 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact I was asked to give a talk on my research at Withington Girls School (and associated schools) in Manchester. The pupils were aged 14-17. They asked lots of really interesting questions and we had discussions afterwards about my research and my career to date. The students were interested in options for different degrees and finding out about higher degrees etc.
Year(s) Of Engagement Activity 2016
 
Description Seminars at UK Institutions 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach National
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact Kings College London (Denmark Hill Campus; vascular tissue engineering)
Manchester (Biochem Soc meeting; elastic fibres)
Bristol University (elastic fibres)
Edinburgh University (progenitor cells)
Keele University (vascular tissue engineering)
Newcastle University (progenitor cells)
Birmingham University (progenitor cells)

Collaborative links.
Year(s) Of Engagement Activity 2008,2009,2010,2011
 
Description The Body Experience 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? Yes
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact We had lots of really good discussions with the general public. We also collected feedback from the event: 'Liked deciding which heart went with which animal. Fascinating learning how skin cells can be made into stem cells', 'Very interesting talk on stents and treatments for heart attacks. All questions answered', 'Really liked the experience. Very informative and fascinating', 'We enjoyed learning about stents and seeing how big different hearts were', 'I liked dressing up like a scientist', 'Learning what is good and bad for your heart', 'I liked looking at the arteries and seeing which one was healthy', 'I liked feeling the hearts.'

Cannot quantify because event was attended by members of the general public and because of the large numbers of people involved.
Year(s) Of Engagement Activity 2013,2014,2015
 
Description The Body Experience, Manchester Museum, March 2016 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact This is an annual event organised by the Faculty of Biology, Medicine and Health at the University of Manchester. I organise the heart and blood vessel activities for the event. We aim is to inform members of the general public about hearts and heart disease and the research conducted within the Institute of Cardiovascular Sciences at the University of Manchester. We run lots of different hands-on activities to demonstrate how the heart and blood vessels work and what goes wrong in disease. Some of the activities also highlight our current research. We always have lots of really good discussions with the general public and obtain fantastic feedback: 'I liked looking at arteries and seeing which one was healthy'; 'I liked crawling through the blood vessels'; 'It was sooooo hard crawling through the diseased vessel'; 'We enjoyed learning about stents and seeing how big different hearts were'; 'I liked dressing up as a scientist'; 'Learning what is good and bad for your heart'; 'Fascinating learning about stem cells'; 'I really want to be a scientist'.
Year(s) Of Engagement Activity 2016
 
Description The Heart Experience - with BHF 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact We had lots of really good discussions with the general public. We also collected feedback from the event: 'Liked deciding which heart went with which animal. Fascinating learning how skin cells can be made into stem cells', 'Very interesting talk on stents and treatments for heart attacks. All questions answered', 'Really liked the experience. Very informative and fascinating', 'We enjoyed learning about stents and seeing how big different hearts were', 'I liked dressing up like a scientist', 'Learning what is good and bad for your heart', 'I liked looking at the arteries and seeing which one was healthy', 'I liked feeling the hearts.'
Year(s) Of Engagement Activity 2015
 
Description The Heart Experience, a public engagement activity at MOSI with the BHF 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact This event is held the Saturday before the BACR conference in Manchester. Its aim is to inform members of the general public about hearts and heart disease and the research conducted within the Institute of Cardiovascular Sciences at the University of Manchester. We run lots of different hands-on activities to demonstrate how the heart and blood vessels work and what goes wrong in disease. Some of the activities also highlight our current research. We always have lots of really good discussions with the general public and obtain fantastic feedback: 'I liked looking at arteries and seeing which one was healthy'; 'I liked crawling through the blood vessels'; 'It was sooooo hard crawling through the diseased vessel'; 'We enjoyed learning about stents and seeing how big different hearts were'; 'I liked dressing up as a scientist'; 'Learning what is good and bad for your heart'; 'Fascinating learning about stem cells'; 'I really want to be a scientist'.
Year(s) Of Engagement Activity 2015,2016
 
Description Wellcome to the Matrix 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Type Of Presentation Workshop Facilitator
Geographic Reach Local
Primary Audience Schools
Results and Impact My MRC lab group contributed to workshops for school childrew for 'Wellcome to the matrix', held in the Faculty of Life Sciences, University of Manchester.

Improved understanding of biology, and encouragement of local school children to take science to the next level.
Year(s) Of Engagement Activity 2013
 
Description Women in Science 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Workshop Facilitator
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact Women in Science open meetin at manchester Museum, to coincide with International Women's Day.

Strong feedback.
Year(s) Of Engagement Activity 2013