BHF Imperial Cardiovascular Regenerative Medicine Centre

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.

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.

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.