MRC-BHF Cardiovascular Stem Cell Research Strategic Development Grant

Lead Research Organisation: Imperial College London
Department Name: National Heart and Lung Institute

Abstract

Heart muscle does not grow back following a heart attack. For this reason, a stem cell approach to regenerate the heart is attractive. We focus on using embryonic stem cells (primitive cells with the ability to become every cell type desired) or a rare and unexpected stem cell we discovered, which exists in heart muscle itself. These experiments are aimed at solving several fascinating and important problems. Where do these cardiac stem cells come from during life, and what do they become in healthy and diseased hearts? Can we improve their number or function to enhance the repair and regeneration of the heart? What specific genes and connections of genes control cardiac muscle creation? Using advanced robotic methods that test hundreds or thousands of conditions, and advanced genetic methods that measure every gene in the cells, we will study which genes are active in heart-forming cells and which are important for the cells function.

Technical Summary

In humans and other mammals, the inability of adult myocardium to overcome cell death with equivalent muscle cell creation makes heart muscle cell number unusually well-posed as a therapeutic target. Notwithstanding a few exemplars, the clinical aspirations arising from this biological limit have led to a plethora of largely repetitive empirical trials with weak outcomes overall, little proven impact on myocyte formation and, typically, weak scientific underpinnings. The need is unequivocal for better, deeper, more systematic knowledge?including genomic, post-genomic and functional characterization of relevant cardiopoietic cells, if a step change is ever to occur in progress towards cardiac regeneration as a workable clinical goal. Inherently, the problem requires a team-based or consortium approach, as is sought by the present MRC-BHF call. This Cardiovascular Stem Cell Research Strategic Development Grant at Imperial College London is a coordinated effort of the National Heart and Lung Institute (NHLI) headed by Professor Michael Schneider FMedSci, an innovative pioneer in cardiovascular stem cell biology, and the MRC Clinical Sciences Centre (CSC) headed by Professor Amanda Fisher FMedSci, a distinguished authority on stem cell epigenetics. Members of the proposed Cardiovascular Stem Cell Research Strategic Development Grant include key experts in mouse genetics, genomics and epigenetics, focused collectively on a series of essential fundamental problems: (1) fate-mapping to define the embryological origin of cardiac progenitor cells and their subsequent contribution to the heart in health and disease; (2) sirtuins and insulin-like growth factor-1 as epigenetic modulators of cardiac repair; (3) chromatin profiling and epigenetic reprogramming of cardiac progenitor cells; (4) high-throughput high-content analyses of cardiac progenitor cell differentiation and function; and (5) next-generation genomics for gene, pathway and chromatin studies in cardiac progenitor cells. A 6,0000 m2 Cardiovascular Research Centre is under construction at Imperial?s Hammersmith campus, adjacent to expanded MRC facilities, and a highly robust recruitment drive is already underway. Apart from the specific questions to be addressed, the overriding goal of this proposal is alignment, integration and capacity-building, establishing an internationally competitive cardiovascular stem cell community that would help lead UK science in this realm and warrant a full-scale Centre in three years? time.

Publications

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Schneider MD (2016) Heartbreak hotel: a convergence in cardiac regeneration. in Development (Cambridge, England)

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Tonkin J (2015) Monocyte/Macrophage-derived IGF-1 Orchestrates Murine Skeletal Muscle Regeneration and Modulates Autocrine Polarization. in Molecular therapy : the journal of the American Society of Gene Therapy

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Yigit G (2015) Mutations in CDK5RAP2 cause Seckel syndrome. in Molecular genetics & genomic medicine

 
Description House of Lords Science and Technology Inquiry on Regenerative Medicine
Geographic Reach National 
Policy Influence Type Gave evidence to a government review
 
Description Member, MRC Council
Geographic Reach National 
Policy Influence Type Participation in advisory committee
 
Description Member, Technology Strategy Board-MRC-EPSRC-BBSRC Advisory Group on Regenerative Medicine (RegenMed)
Geographic Reach National 
Policy Influence Type Gave evidence to a government review
Impact Led to the funding of multiple industry-led projects in regenerative medicine, as well as to the overall UK Strategy for Regenerative Medicine
 
Description 4-Year PhD Studentship Scheme
Amount £2,500,000 (GBP)
Organisation British Heart Foundation (BHF) 
Sector Charity/Non Profit
Country United Kingdom
Start  
 
Description BHF Centre of Research Excellence
Amount £3,000,000 (GBP)
Funding ID RE/08/002 (renewal) 
Organisation British Heart Foundation (BHF) 
Sector Charity/Non Profit
Country United Kingdom
Start  
 
Description Cardiovascular Biomedical Research Unit
Amount £9,740,780 (GBP)
Organisation National Institute for Health Research 
Department NIHR Imperial Biomedical Research Centre
Sector Academic/University
Country United Kingdom
Start  
 
Description Comprehensive Biomedical Research Centre - Cardiovascular Theme
Amount £3,316,082 (GBP)
Organisation National Institute for Health Research 
Department NIHR Imperial Biomedical Research Centre
Sector Academic/University
Country United Kingdom
Start  
 
Description Confidence in Concepts Fund
Amount £78,403 (GBP)
Funding ID CiC 2012 (MC_PC_12015) 
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start  
 
Description Early Stage Seeding Drug Discovery Grant
Amount £2,500,000 (GBP)
Funding ID WT106328 
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 03/2015 
End 02/2017
 
Description Late Stage Seeding Drug Discovery Award
Amount £4,500,000 (GBP)
Funding ID 205256/Z/16/Z 
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 05/2017 
End 11/2019
 
Description MRC Confidence-in-Concept
Amount £80,000 (GBP)
Funding ID MC_PC_16046 
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start  
 
Description MRI Pilot Project
Amount £10,000 (GBP)
Organisation British Heart Foundation (BHF) 
Sector Charity/Non Profit
Country United Kingdom
Start  
 
Description Strategic Initiative - Funds toward building and equipping the Hammersmith Campus L Block facility, Imperial College London
Amount £6,000,000 (GBP)
Funding ID SI/11/2/28875 
Organisation British Heart Foundation (BHF) 
Sector Charity/Non Profit
Country United Kingdom
Start  
 
Description UK Cardiovascular Regenerative Medicine Centre
Amount £2,500,000 (GBP)
Funding ID RM/13/1/30157 
Organisation British Heart Foundation (BHF) 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2013 
End 09/2018
 
Title Cardiac stem cell lines 
Description Novel adult cardiac stem cell lines generated from Sca-1+ side population cells, Sca-1+ PDGFRa+ cells, and other sub-populations 
Type Of Material Cell line 
Year Produced 2011 
Provided To Others? Yes  
Impact Demonstration that physical substrate affects nuclear histone deactylase content in cardiac stem cells (with materials scientist Molly Stevens, Imperial Faculty of Engineering) Demonstration of epigenetic mechanisms affecting the cardiac cell fate in cardiac stem cells (DNA methylation: with Tim Aitman, MRC CSC; histone marks and RNA-Seq, with Ana Pombo, MRC CSC) Demonstration that the cardiac stem cells can rescue human stem cell-derived cardiomyocytes from lethal oxidative stress, via secreted signals. Global transcriptomic and proteomic studies are in progress. Interim studies of several dozen candidate factors have identified roughly a half dozen whose presence correlates strongly with the observed cardiac muscle cell protection. Demonstration that the cardiac stem cells can suppress M1 macrophage polarisation and promote M2 macrophage polarisation, via secreted signals. 
URL https://www.bhf.org.uk/news-from-the-bhf/news-archive/2015/may/stem-cell-injection
 
Title Novel inhibitors of MAP4K4 
Description Highly specific small molecular inhibitors of MAP4K4 that suppress cardiac muscle cell death 
Type Of Material Technology assay or reagent 
Provided To Others? No  
Impact The inhibitors of MAP4K4 suppress human cardiac muscle cell death, using induced pluripotent cell-derived cardiomyocytes. 
URL http://www3.imperial.ac.uk/newsandeventspggrp/imperialcollege/newssummary/news_13-4-2015-12-55-43
 
Description AZ CSC screen 
Organisation AstraZeneca
Country United Kingdom 
Sector Private 
PI Contribution Evaluating compounds and pathways for driving the differentiation of dormant stem cells purified from adult mouse myocardium; unique cells and assay methods
Collaborator Contribution Provision of a well-characterised and annotated compound library, including proprietary agents; shared information and technical advice
Impact Not as yet
Start Year 2016
 
Description Novel small molecule inhibitors of MAP4K4 to suppress cardiac muscle cell death 
Organisation Domainex
Country United Kingdom 
Sector Private 
PI Contribution My laboratory identified MAP4K4 (an upstream member of the MAP kinase superfamily) as a potential nodal control point for cardiac muscle cell death, based on (1) biochemical analyses of severe human heart failure, four mouse models of heart disease, and cultured cardiomyocytes subjected to four specific death signals; (2) gain-of-function mutations in mouse myocardium and cultured cardiomyocytes, which potentiate or suffice to drive cell death; (3) dominant-negative mutations and RNA interference in cultured cardiomyocytes, which confer significant protection from cell death. Together with colleagues in Imperial's Drug Discovery Centre, we initiated cell-free screens for novel inhibitors of MAP4K4, through 3D field-point modelling of features conserved among the seemingly unrelated primary hits. The field point model was used to screen 3.7 million structures in silica, 45 compounds were tested against human MAP4K4. The best was used as the founding member of a chemical series via structure-driven drug design, which from the start had high potency, selectivity, and in-cell activity measured as human cardiomyocyte protection from lethal oxidative stress. Compounds with, in addition, suitable stability and solubility were taken forward into mice, and reduced infarct size by more than 50%. Exploratory toxicology studies have been encouraging. Large mammal pharmacokinetics and efficacy studies are underway,
Collaborator Contribution MRC Protein Phosphorylation Unit: Kinase selectivity profiling Domainex: Medicinal chemistry strategy, docking model, computer-assisted drug design, current site for cell free assays, partner organisation for the successful £2.5M Wellcome Trust Early Stage Seeding Drug Discovery Award and £7M Wellcome Trust Late Stage Seeding Drug Discovery Award. Erasmus University: large mammal studies
Impact Cardiovascular biology, chemical biology, clinical cardiology, medicinal chemistry, molecular and cellular biology, molecular physiology
Start Year 2012
 
Description Novel small molecule inhibitors of MAP4K4 to suppress cardiac muscle cell death 
Organisation University of Dundee
Department MRC Protein Phosphorylation and Ubiquitylation Unit
Country United Kingdom 
Sector Public 
PI Contribution My laboratory identified MAP4K4 (an upstream member of the MAP kinase superfamily) as a potential nodal control point for cardiac muscle cell death, based on (1) biochemical analyses of severe human heart failure, four mouse models of heart disease, and cultured cardiomyocytes subjected to four specific death signals; (2) gain-of-function mutations in mouse myocardium and cultured cardiomyocytes, which potentiate or suffice to drive cell death; (3) dominant-negative mutations and RNA interference in cultured cardiomyocytes, which confer significant protection from cell death. Together with colleagues in Imperial's Drug Discovery Centre, we initiated cell-free screens for novel inhibitors of MAP4K4, through 3D field-point modelling of features conserved among the seemingly unrelated primary hits. The field point model was used to screen 3.7 million structures in silica, 45 compounds were tested against human MAP4K4. The best was used as the founding member of a chemical series via structure-driven drug design, which from the start had high potency, selectivity, and in-cell activity measured as human cardiomyocyte protection from lethal oxidative stress. Compounds with, in addition, suitable stability and solubility were taken forward into mice, and reduced infarct size by more than 50%. Exploratory toxicology studies have been encouraging. Large mammal pharmacokinetics and efficacy studies are underway,
Collaborator Contribution MRC Protein Phosphorylation Unit: Kinase selectivity profiling Domainex: Medicinal chemistry strategy, docking model, computer-assisted drug design, current site for cell free assays, partner organisation for the successful £2.5M Wellcome Trust Early Stage Seeding Drug Discovery Award and £7M Wellcome Trust Late Stage Seeding Drug Discovery Award. Erasmus University: large mammal studies
Impact Cardiovascular biology, chemical biology, clinical cardiology, medicinal chemistry, molecular and cellular biology, molecular physiology
Start Year 2012
 
Description Annual Clinical School Lecture, Cambridge Medical Society, Addenbrooks Hospital, Cambridge 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Health professionals
Results and Impact 50 Cambridge alumni and partners attended lecture, with lively discussion afterwards

not reported
Year(s) Of Engagement Activity 2011
 
Description BHF Supporters Day (London) 
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 Supporters
Results and Impact Hosted and lectured at the regional annual South of England symposium for BHF supporters
Year(s) Of Engagement Activity 2016
URL https://www.bhf.org.uk/get-involved/in-your-area/supporter-conferences
 
Description Conference invited talk 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Postgraduate students
Results and Impact conference presentation
Year(s) Of Engagement Activity 2017
 
Description Daily Mail interview ("Jab that can trick the heart into healing itself could be given to coronary victims in back of ambulances") 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Was interviewed by Fiona Macrae about our work on dormant stem cells in adult heart tissue

Circulation 1.9M; 203 "likes" on Facebook
Year(s) Of Engagement Activity 2012
URL http://www.dailymail.co.uk/health/article-2207630/The-jab-trick-heart-heal-itself.html
 
Description Lecture to the Friends of Imperial ("The Self-healing Heart") 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Type Of Presentation Keynote/Invited Speaker
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact Thirty lay adults attended an evening behind the scenes in Imperial's cardiovascular laboratories, preceded by a lecture on cardiac regeneration and stem cell biology.
Year(s) Of Engagement Activity 2014
 
Description Newspaper article - The Times ("A question of visas and world talent") 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Circulation 508K

Not known
Year(s) Of Engagement Activity 2010
 
Description Online chatroom (Heart Zone, imascientist.org.uk) 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? Yes
Geographic Reach National
Primary Audience Schools
Results and Impact stimulated active Q&A with diverse student groups

Organisers were pleased with the level of student animation by the sessions and sought my further involvement for future activities.
Year(s) Of Engagement Activity 2015
URL http://imascientist.org.uk
 
Description Online webcast and transcript (House of Lords Select Committee on Science and Technology Inquiry on Regenerative Medicine) 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? Yes
Type Of Presentation Keynote/Invited Speaker
Geographic Reach International
Primary Audience Policymakers/politicians
Results and Impact online webcast and transcript

Contributed to the resulting House of Lords Select Committee Report on Regenerative Medicine (2013)
Year(s) Of Engagement Activity 2012
 
Description Podcast (Understanding Animal Research) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact online interview

not known
Year(s) Of Engagement Activity 2012
URL http://www.understandinganimalresearch.org.uk/resources/video-library/24/stem-cells-and-heart-repair...
 
Description RCUK Research, Innovate, Grow event (Westminster) 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Policymakers/politicians
Results and Impact Presented the MRC Regenerative Medicine programme to BIS Minister Jo Johnson, business leaders, entrepreneurs, world-leading researchers, parliamentarians and policymakers, as part of a Research Councils UK event
Year(s) Of Engagement Activity 2015
URL http://www.rcuk.ac.uk/rig/
 
Description Recurring lay visits 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact Recurring visits of potential high-value British Heart Foundation donors, in support of the Mending Broken Hearts capital campaign

BHF reports lay visitor enthusiasm and appreciation for regenerative medicine initiative
Year(s) Of Engagement Activity 2011,2012,2013,2014
 
Description Science in Store (Ealing) 
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 Simple play-oriented science demonstration about heart muscle cell structure and electrical connectivity, for primary-school-age children and families. This successful activity module is being disseminated to other public engagement activities. Discussion/Q&A with parents, patients.
Year(s) Of Engagement Activity 2017
URL https://www.bhf.org.uk/get-involved/events/social-events/science-in-store
 
Description iTunes video interview - Imperial 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Online interview on cardiac stem cell biology & regenerative medicine. Available through iTunes.

Not known
Year(s) Of Engagement Activity 2012