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

Aarts M
(2017)
Coupling shRNA screens with single-cell RNA-seq identifies a dual role for mTOR in reprogramming-induced senescence.
in Genes & development

Adamowicz M
(2018)
Functionally Conserved Noncoding Regulators of Cardiomyocyte Proliferation and Regeneration in Mouse and Human.
in Circulation. Genomic and precision medicine

Belian E
(2015)
Forward Programming of Cardiac Stem Cells by Homogeneous Transduction with MYOCD plus TBX5.
in PloS one

Buyandelger B
(2015)
ZBTB17 (MIZ1) Is Important for the Cardiac Stress Response and a Novel Candidate Gene for Cardiomyopathy and Heart Failure.
in Circulation. Cardiovascular genetics

Fiedler LR
(2019)
MAP4K4 Inhibition Promotes Survival of Human Stem Cell-Derived Cardiomyocytes and Reduces Infarct Size In Vivo.
in Cell stem cell

Földes G
(2014)
Immunosuppressive agents modulate function, growth, and survival of cardiomyocytes and endothelial cells derived from human embryonic stem cells.
in Stem cells and development

Földes G
(2011)
Modulation of human embryonic stem cell-derived cardiomyocyte growth: a testbed for studying human cardiac hypertrophy?
in Journal of molecular and cellular cardiology

Gallego-Colon E
(2015)
Cardiac-Restricted IGF-1Ea Overexpression Reduces the Early Accumulation of Inflammatory Myeloid Cells and Mediates Expression of Extracellular Matrix Remodelling Genes after Myocardial Infarction.
in Mediators of inflammation

Gallego-Colon E
(2016)
Intravenous delivery of adeno-associated virus 9-encoded IGF-1Ea propeptide improves post-infarct cardiac remodelling.
in NPJ Regenerative medicine

Hasham MG
(2017)
Systemic autoimmunity induced by the TLR7/8 agonist Resiquimod causes myocarditis and dilated cardiomyopathy in a new mouse model of autoimmune heart disease.
in Disease models & mechanisms
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 | Public |
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 | Public |
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 | Public |
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 | Public |
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 | Academic/University |
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 |