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.

Publications

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Bagdadi AV (2018) Poly(3-hydroxyoctanoate), a promising new material for cardiac tissue engineering. in Journal of tissue engineering and regenerative medicine

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Breckwoldt K (2016) Heart regeneration. in Biochimica et biophysica acta

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Dixon JE (2016) Highly efficient delivery of functional cargoes by the synergistic effect of GAG binding motifs and cell-penetrating peptides. in Proceedings of the National Academy of Sciences of the United States of America

 
Description Special advisor to the House of Commons Science and Technology Select Committee report on Regenerative Medicine
Geographic Reach National 
Policy Influence Type Participation in a national consultation
 
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 10/2016 
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 10/2013 
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 Charity/Non Profit
Country United Kingdom
Start 10/2013 
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 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 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 10/2016 
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 04/2014 
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
 
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 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 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 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