BHF Imperial Cardiovascular Regenerative Medicine Centre
Lead Research Organisation:
Imperial College London
Department Name: National Heart and Lung Institute
Abstract
The BHF UK Regenerative Medicine Centre at Imperial College and Nottingham focuses on the heart muscle cell, and there are two main aspects to the research. First, patient-derived blood or skin cells can be turned into beating heart muscle cells, and it has been shown that they can have the characteristics of the heart disease seen in the patient. This allows us to investigate them as a "disease-in-a-dish" model and work out drug treatments or gene therapy specific for that type of patient. One very useful aspect of the stem cells is the ability to grow them in large numbers. To take advantage of that, new machines are being developed to screen multiple cells simultaneously. Both Imperial and Nottingham have experience in designing these large-scale experiments. We wish to purchase a number of state-of-the-art machines, shared between Imperial and Nottingham; develop cell models and assays for these; then make them available to the Regenerative Medicine community. Second, we aim to make muscle grafts from the stem cell-derived heart cells and to implant them in disease models in rats and mice to assess whether they will provide repair. We have used an MRI machine to do this previously, but ours has been decommissioned. We are asking for a contribution to the purchase of another MRI, and for its housing at Imperial in the building where the majority of Cardiovascular Regenerative Medicine researchers work, and next to other imaging machines which we will also use.
Technical Summary
We plan a suite of high content/automated imaging platforms for the assessment of the cardiomyocyte phenotype with complementary capabilities at Imperial and Nottingham. This will allow complete phenotyping of a given endogenous, reprogrammed or pluripotent-stem cell derived cardiomyocyte by the Imperial/Nottingham Centre. The cardiomyocyte from embryonic (hESC-CM) or induced pluripotent (iPSC-CM) stem cells represents a human genotype-specific cell with an authentic morphological, electrical and contractile phenotype. For investigation of development, disease modelling and target discovery, the high throughput capabilities of stem cell-derived cardiomyocytes have the potential to produce a step-change in scale for the cardiac cell biology researcher. This will mesh with the increasing number of small- and large-scale initiatives to produce patient-derived pluripotent stem cells to model cardiac disease. Academics will also be well placed to transfer laboratory-based medium-throughput studies directly to Industry assays where similar platforms are used. We also ask for a contribution to the purchase and housing of new MRI scanner which will replace the instrument previously supported by the MRC CSC at Imperial. The proposed site for the MRI is the basement of the Imperial Centre for Translational and Experimental Medicine (ICTEM), where the majority of Imperial PIs are based. The proposed new facility will house Magnetic Resonance (MR), Positron Emission Tomography - Computed Tomography (PET-CT) and In-Vivo Imaging System (IVIS) scanning equipment together with associated support areas. The MRI is essential for the phenotyping of animals after interventions to increase cardiac stem-cell derived muscle integration, and we have developed state-of-the-art image analysis algorithms for these experiments in rodent disease models.
Planned Impact
The immediate beneficiary in terms of health is the cardiovascular patient population. Collectively, heart and circulatory diseases cause more than a quarter of all deaths in the UK, accounting for more than 159,000 deaths each year. The cost of premature death, lost productivity, hospital treatment and prescriptions is estimated at £19 billion. The primary reason for the decline into heart failure is loss of the muscle capacity of the heart, and the effectiveness of Left Ventricular Assist Devices shows that restoring power keeps the patient alive. Our centre aims focuses of the degeneration into heart failure and aims to address the problem of preparing and maintaining the cardiac graft, or stimulating the natural repair processes. This will have relevance for the 750,000 or more people living with heart failure in the UK.
The development of the iPSC-CM as a tool for target and drug discovery has potential to widen the benefitting group to all aetiologies of disease and to build a bridge between the researcher and the pharmaceutical industry. Assays for high throughput screening developed in an academic laboratory can be transferred directly to the companies. Genotype-specific solutions points the way to a stratified medicine strategy, increasing the effectiveness of therapy. As well as this, the off-target effects of non-cardiac drugs to produce cardiotoxicity, a known problem for industry, can be addressed. The success of models of long QT syndrome has pointed the way, and now the cardiotoxic effects of cancer chemotherapeutic agents is being studied extensively. This will be of importance in the cancer survivor cohort who are increasingly long-lived.
The development of the iPSC-CM as a tool for target and drug discovery has potential to widen the benefitting group to all aetiologies of disease and to build a bridge between the researcher and the pharmaceutical industry. Assays for high throughput screening developed in an academic laboratory can be transferred directly to the companies. Genotype-specific solutions points the way to a stratified medicine strategy, increasing the effectiveness of therapy. As well as this, the off-target effects of non-cardiac drugs to produce cardiotoxicity, a known problem for industry, can be addressed. The success of models of long QT syndrome has pointed the way, and now the cardiotoxic effects of cancer chemotherapeutic agents is being studied extensively. This will be of importance in the cancer survivor cohort who are increasingly long-lived.
Publications
Watson SA
(2019)
Biomimetic electromechanical stimulation to maintain adult myocardial slices in vitro.
in Nature communications
Van Meer BJ
(2019)
Simultaneous measurement of excitation-contraction coupling parameters identifies mechanisms underlying contractile responses of hiPSC-derived cardiomyocytes.
in Nature communications
Vaithilingam J
(2019)
Multifunctional Bioinstructive 3D Architectures to Modulate Cellular Behavior
in Advanced Functional Materials
Trantidou T
(2015)
Biorealistic cardiac cell culture platforms with integrated monitoring of extracellular action potentials.
in Scientific reports
Trantidou T
(2016)
Surface Chemistry and Microtopography of Parylene C Films Control the Morphology and Microtubule Density of Cardiac Myocytes.
in Tissue engineering. Part C, Methods
Suzuki K
(2016)
Five colour variants of bright luminescent protein for real-time multicolour bioimaging.
in Nature communications
Smith JGW
(2018)
Isogenic Pairs of hiPSC-CMs with Hypertrophic Cardiomyopathy/LVNC-Associated ACTC1 E99K Mutation Unveil Differential Functional Deficits.
in Stem cell reports
Sattler S
(2017)
The adaptive immune response to cardiac injury-the true roadblock to effective regenerative therapies?
in NPJ Regenerative medicine
Saleem U
(2020)
Force and Calcium Transients Analysis in Human Engineered Heart Tissues Reveals Positive Force-Frequency Relation at Physiological Frequency.
in Stem cell reports
Saleem U
(2020)
Blinded, Multicenter Evaluation of Drug-induced Changes in Contractility Using Human-induced Pluripotent Stem Cell-derived Cardiomyocytes.
in Toxicological sciences : an official journal of the Society of Toxicology
Title | Art in Science image exhibition in Nottingham |
Description | A public exhibition on outdoor display around Nottingham County Council's Highfields Park. Each of the 27 boards at A0 size displayed a stunning science image, highlighted the researcher and contained 3 simple messages on 1) the medical problem, 2) what we are doing to solve it, 3) what the science image shows. This exhibition has been on display for 6 months so far and the Park has an average monthly footfall of around 50,000 people. In parallel, the images have been used to promote research through social media over a 6 month period, including on Twitter and Instagram |
Type Of Art | Image |
Year Produced | 2021 |
Impact | Greater appreciation of the science this is conducted at the University of Nottingham and just how beautiful scientific 'inner space' can be, hence the title of Art in Science |
Description | BHF Clinical Research Training Fellowship |
Amount | £152,776 (GBP) |
Funding ID | FS/15/79/31736 |
Organisation | British Heart Foundation (BHF) |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 01/2016 |
End | 12/2017 |
Description | BHF Clinical Research Training Fellowship - Richard Jabbour: |
Amount | £215,481 (GBP) |
Funding ID | FS/16/17/31663 |
Organisation | British Heart Foundation (BHF) |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 09/2016 |
End | 09/2019 |
Description | BHF UK cardiovascular Regenerative Medicine Centre |
Amount | £2,500,000 (GBP) |
Organisation | British Heart Foundation (BHF) |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 09/2013 |
End | 09/2017 |
Description | CRACKIT Scheme |
Amount | £100,000 (GBP) |
Organisation | National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs) |
Sector | Public |
Country | United Kingdom |
Start | 09/2013 |
End | 05/2014 |
Description | Crack It Mini Challenge : Monitoring contractility of bio-realistic human cardiac tissue in vitro |
Amount | £100,000 (GBP) |
Funding ID | NC/C013106/1 |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start | 01/2014 |
End | 07/2014 |
Description | Do snoRNAs govern genotype-phenotype interactions in hypertrophic cardiomyopathy? |
Amount | £1,000,000 (GBP) |
Funding ID | SP/F/22/150044 |
Organisation | British Heart Foundation (BHF) |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 05/2023 |
End | 05/2028 |
Description | MRC Capital call for Regenerative Medicine |
Amount | £714,000 (GBP) |
Funding ID | MR/L012618/1 |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start | 01/2014 |
End | 04/2014 |
Description | MRC Programme Grant MR/W016176/1: Exploiting a novel molecular toolkit to explore cell type specific adenosine receptor pharmacology and regulation at endogenous levels of expression. £2M 2022-2027. PI Steve Hill. Co-Is: Chris Denning, Jeanette Woolard, |
Amount | £2,000,000 (GBP) |
Funding ID | MR/W016176/1 |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start | 05/2022 |
End | 05/2027 |
Description | MRC-AIM iCASE studentship joint with GlaxoSmithKline and AstraZeneca. Unravelling drug-gene-phenotype interactions in complex cardiovascular diseases: A PhD studentship co-sponsored iCASE with AstraZeneca (AZ) & GlaxoSmithKline (GSK) |
Amount | £200,000 (GBP) |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start | 09/2022 |
End | 09/2026 |
Description | Mechanisms of arrhythmia generation from implanted stem cell-derived cardiomyocytes in infarcted hearts |
Amount | £215,481 (GBP) |
Funding ID | FS/16/17/31663 |
Organisation | British Heart Foundation (BHF) |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 09/2016 |
End | 10/2019 |
Description | UK Regenerative Medicine Platform |
Amount | £500,000 (GBP) |
Funding ID | MR/L022699/1 |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start | 03/2014 |
End | 03/2017 |
Description | UK-China Stem Cell Partnership Initiative |
Amount | £487,000 (GBP) |
Funding ID | MR/M010422/1 |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start | 01/2015 |
End | 01/2018 |
Description | iPSC-derived cardiomyocytes to model estrogen receptor modulation of stress cardiomyopathy and arrhythmic syndromes |
Amount | £343,557 (GBP) |
Funding ID | MR/M010422/1 |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start | 01/2015 |
End | 06/2018 |
Description | • BBSRC iCASE studentship joint with GlaxoSmithKline. Development of multiparametric kinetic data and analytics workflows for the generation of an hiPSC-cardiomyocyte based cardiovascular model. PI, Denning. £120K. Oct 2019 to Jan 2024 |
Amount | £120,000 (GBP) |
Organisation | GlaxoSmithKline (GSK) |
Sector | Private |
Country | Global |
Start | 09/2019 |
End | 01/2024 |
Description | • BHF: CRMR/21/290009: Renewed Funding for the BHF Centres of Regenerative Medicine. 1.10.21 to 30.09.2024. £1,540,553 of which £475,165 to Denning as UoN PI |
Amount | £475,000 (GBP) |
Funding ID | CRMR/21/290009 |
Organisation | British Heart Foundation (BHF) |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 09/2021 |
End | 09/2024 |
Description | • BHF: PG/21/10545. Evaluating the role of novel loci in hypertrophic cardiomyopathy. 05-01-2022 to 04-01-2025. £301,755. Denning, PI |
Amount | £301,755 (GBP) |
Funding ID | PG/21/10545 |
Organisation | British Heart Foundation (BHF) |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 01/2022 |
End | 01/2025 |
Description | • MRC-AIM iCASE studentship joint with GlaxoSmithKline and AstraZeneca. Unravelling drug-gene-phenotype interactions in complex cardiovascular diseases: A PhD studentship co-sponsored iCASE with AstraZeneca (AZ) & GlaxoSmithKline (GSK) - PhD Application. |
Amount | £120,000 (GBP) |
Organisation | GlaxoSmithKline (GSK) |
Sector | Private |
Country | Global |
Start | 09/2022 |
End | 09/2026 |
Description | • UKRI. Grant code: TBC. Asymptomatic Covid-19 in Education (ACE) Immunity Study. PI Lucy Fairclough. Denning at Co-I. 1 Jun 2021 - 31 Mar 2022. £506,648 |
Amount | £506,648 (GBP) |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start | 05/2021 |
End | 03/2022 |
Title | Ultrathin tissue slices |
Description | Slices of human or animal myocardium maintained fully viable in culture for p to 5 days, with ability to generate force |
Type Of Material | Model of mechanisms or symptoms - in vitro |
Year Produced | 2017 |
Provided To Others? | Yes |
Impact | Drug discovery tool and investigation method to understand graft integration to myocardium |
URL | https://www.ncbi.nlm.nih.gov/pubmed/29189769 |
Description | Human Cell Atlas |
Organisation | The Wellcome Trust Sanger Institute |
Country | United Kingdom |
Sector | Charity/Non Profit |
PI Contribution | Provision of human cells and nuclei from heart |
Collaborator Contribution | Deep and large scale analysis of the single cell DNA, RNA and protein content |
Impact | n/a |
Start Year | 2017 |
Description | Art in Science: Community Workshops |
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 | Communicating science through the use of arts and textile to Nottinghamshire communities |
Year(s) Of Engagement Activity | 2022 |
URL | https://city-arts.org.uk/project/heart/ |
Description | Art in Science: Exhibition event |
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 | Open forum to show how art and science can come together and enhance understanding of both disciplines |
Year(s) Of Engagement Activity | 2022 |
Description | Art in Science: Festival of Science & Curiosity |
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 | Nottinghamshire-wide Festival of Science & Curiosity to expand knowledge and engagement of science |
Year(s) Of Engagement Activity | 2023 |
URL | https://nottsfosac.co.uk/ |
Description | Art in Science: Science in the Park |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Public/other audiences |
Results and Impact | Science in the Park attracts national audiences to explore different types of science, with an emphasis on family participation and engagement |
Year(s) Of Engagement Activity | 2023 |
URL | https://wollatonhall.org.uk/science-in-the-park/ |
Description | BBC4: • The Secrets of Size: Going Small on BBC4 Monday 16th May 2022 |
Form Of Engagement Activity | A broadcast e.g. TV/radio/film/podcast (other than news/press) |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Public/other audiences |
Results and Impact | Part of the BBC4 series on Secrets of Size. Our contribution was on how stem cells can be converted into heart cells to an audience of millions |
Year(s) Of Engagement Activity | 2022 |
URL | https://www.bbc.co.uk/programmes/m0017frp |
Description | BHF Science in Store |
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 | Designing and setting up activities in a BHF Furniture store. Towards a potential UK-wide initiative |
Year(s) Of Engagement Activity | 2017 |
Description | BHF Sponsor day Nov 2023 |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Public/other audiences |
Results and Impact | Engaged as keynote speaker at BHF sponsor event, attended by approx 100 people - great questions at event and very engaged audience |
Year(s) Of Engagement Activity | 2023 |
Description | BHF regional visits |
Form Of Engagement Activity | Participation in an open day or visit at my research institution |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Supporters |
Results and Impact | Visit from regional and national fundraisers to hear and understand more about our research and facilities |
Year(s) Of Engagement Activity | 2023 |
Description | BHF shop opening in Bullwell |
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 | Opened BHF store in Bullwell, Nottinghamshire, and discussed stem cell research with the public |
Year(s) Of Engagement Activity | 2023 |
Description | COVID testing: SkyNews, BBC News, BBC East Midlands Today. Throughout 2020, 2021, 2022. Audience size, millions |
Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Media (as a channel to the public) |
Results and Impact | The University of Nottingham COVID Asymptomatic Testing Service used sensitive PCR approaches on non-invasive saliva samples. I led the Service, including to accreditation by the UK Accreditation Service. More than 150,000 samples were processed, which helped keep the UoN campuses open during the pandemic. This activity built on the research techniques used in my lab. The Service attracted considerable media interest, including visits and pieces done by SkyNews, BBC National News, BBC East Midlands Today, Radio Nottingham, and was raised during Parliamentary debates in the House of Commons |
Year(s) Of Engagement Activity | 2020,2021,2022 |
URL | https://www.nottingham.ac.uk/coronavirus/university-testing-service/index.aspx |
Description | Cross parliamentary discussion on the important of non-animal technologies |
Form Of Engagement Activity | A formal working group, expert panel or dialogue |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Policymakers/politicians |
Results and Impact | Cross parliamentary discussion on the importance of non-animal technologies to inform politicians of the need, and how, to progress this area of research |
Year(s) Of Engagement Activity | 2021 |
Description | Festival of Science & Curiosity 2024 |
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 | Presented the HeART project of public engagement to attendees of Nottingham's Festival of Science & Curiosity, using hands-on workshop with creative materials to promote interaction |
Year(s) Of Engagement Activity | 2024 |
Description | Filming of patient (Celia) in Oct 2023 |
Form Of Engagement Activity | Participation in an open day or visit at my research institution |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Patients, carers and/or patient groups |
Results and Impact | A day with a patient discussing the perspective from the patient's point of view and showing them our research |
Year(s) Of Engagement Activity | 2023 |
Description | HeART library project |
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 | Ran 10 workshops when school children were bused into Clifton Library in Nottingham and taught about stem cells and heart disease. They were shown how to create textiles so that they could interpret what they had been taught through creativity and art. This led to a gargantuan book being created, which is now exhibited at Nottingham's new Central Library |
Year(s) Of Engagement Activity | 2023,2024 |
Description | Heart and Lung Convenience Store |
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 | 2 week pop up shop in local Mall |
Year(s) Of Engagement Activity | 2015 |
Description | Heart and Lung Repair Shop |
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 | A retail unit in Kings Mall Hammersmith was converted into a shop to engage the public in activities around our research. It was staffed 11-5pm with evening activities also. I manned this for several days and one evening More than 2000 visitors of all ages came to the shop and the various demonstrations. |
Year(s) Of Engagement Activity | 2014 |
Description | Maastricht will host the 11th World Congress on Alternatives and Animal Use in the Life Sciences. August 2021 |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Panel speaker at Maastricht will host the 11th World Congress on Alternatives and Animal Use in the Life Sciences. August 2021 |
Year(s) Of Engagement Activity | 2021 |
URL | https://www.eslav.org/events/11th-world-congress-on-alternatives-and-animal-use-in-the-life-sciences... |
Description | Pig to human heart transplant: Radio 4; GB News. Feb 2022. Audience size, millions |
Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Media (as a channel to the public) |
Results and Impact | Interview on the pros and cons of the first ever pig to human heart transplant |
Year(s) Of Engagement Activity | 2022 |
URL | https://www.bbc.co.uk/programmes/m00146c3 |
Description | Pint of Science 2022 |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Public/other audiences |
Results and Impact | • Pint of Science: The Waterfront (under show title- "The day we find the cure"). |
Year(s) Of Engagement Activity | 2022 |
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 | 80 pupils attended a session on STEM |
Year(s) Of Engagement Activity | 2018 |
Description | Undercover COVID. Lead expert witness for BBC Panorama. April 2021. Audience size, millions |
Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Media (as a channel to the public) |
Results and Impact | I was the lead expert on "BBC Panorama undercover inside the testing lab", which exposed awful practices, false results and risk to the public |
Year(s) Of Engagement Activity | 2021 |
URL | https://www.bbc.co.uk/programmes/m000tqjj |
Description | University of the third Age (U3A) |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Public/other audiences |
Results and Impact | Exploring with audiences from U3A on science, ethics and public engagement |
Year(s) Of Engagement Activity | 2023 |