BHF Centre for Vascular Regeneration
BHF Centre for Vascular Regeneration
Background to the CVR
Ischaemic heart disease (IHD) is the leading cause of death worldwide, accounting for over 17 million deaths annually (1). The mortality from acute myocardial infarction (MI) has improved significantly and in the United Kingdom 70% or more of the 188,000 patients who suffer from MI each year survive. Modern treatments for chronic angina, involving epicardial coronary artery revascularisation or bypass by percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG) respectively, are also very effective. The major challenge, however, is the management and treatment of patients who develop chronic heart failure (CHF) in the weeks, months and years after MI due to progressive left ventricular (LV) remodelling. The incidence of ischaemic CHF has reached epidemic proportions, accounting for an estimated 26 million people worldwide and resulting in more than 1 million hospital episodes annually in the USA and Europe (2). These patients have poor life expectancy and around 20% do not survive past one year. For end-stage ischaemic CHF the mortality rate is about 50% by 5 years, accounting for 70,000 annual deaths in the UK (3, 4). Although there are several medical and device therapies that make a modest impact on this mortality, CHF is an inexorable and largely irreversible condition that is in desperate need of new preventive and therapeutic approaches (5).
1. Organistation WH. Global Health Observatory data repository ‘Mortality and global health estimates’ 2008 [http://apps.who.int/gho/data/node.home#. 2. Ambrosy A, et al. JACC. 2014;63(12):1123-33. 3. Coleman M, F et al. The Lancet. 2011;377(9760):127-38. 4. Townsend N, et al. Cardiovascular Disease Statistics: British Heart Foundation; 2014. 5. Yancy C, J et al. Circulation. 2013;62(16):147-239.
Mission of the CVR
The Centre will focus specifically on therapies that target neovascularization and improved infarct repair early after MI. We will identify the most effective treatments, both by studying the mechanisms by which they modulate tissue-resident and circulating cells during myocardial revascularisation and repair, and by studying their phenotype and function in large animal models of MI that more closely represent the human condition. Moreover, strategies to activate endogenous mechanisms associated with neovasculogenesis, and via recruitment of circulating endothelial progenitors to promote repair both directly and by paracrine signals, may offer bona fide clinical benefit.
Aims and Objectives of the CVR
Theme 1: Exploration of endogenous endothelial origin, fate and plasticity post-MI. Theme 2: Studies to define novel exogenous endothelial mechanisms and therapies. Theme 3: Research defining the origin and plasticity of mesenchymal cells post-MI. Theme 4: Testing three GMP-compatible therapeutic strategies in the pig acute MI model for cardiovascular repair.
Theme 1: Activation of endogenous vascular regeneration. PIs: Randi, Brittan (Co-leads), Mills, Shah, Baker, Mayr, Henderson.
- To identify the transcriptional and epigenetic pathways underlying the regenerative function of circulating progenitor cells (BOEC).
- To define endogenous EC pathways promoting neovascularisation and regeneration.
- To provide in vitro and in vivo functional validation of EC regeneration pathways.
Theme 2: Exogenous vascular regeneration PIs: Emanueli (lead) Baker, Henderson, Mayr.
- Investigate the therapeutic potential of established hESC-EC in rodent MI.
- Promote arterial and lymphatic specification of hESC-EC and assess the impact of transplanted hESC-AEC and -LEC on post-MI vascular regeneration.
- Investigate the contribution of EV to the therapeutic responses to hESC-ECs.
- Develop bioinspired synthetic exosomes as off-the-shelf therapeutics to induce vascular regeneration in the setting of MI.
Theme 3: Targeting the cardiac mesenchyme to drive regeneration post-MI. PIs: Henderson, Madeddu (co-leads) Mayr, Shah.
- Investigate the functional phenotype of cardiac mesenchymal cell subpopulations in health and disease giving rise to vascular smooth muscle cells (VSMC) or fibroblasts.
- Identify and characterise the pro-reparative mesenchymal subpopulations post-MI using a single cell RNA sequencing approach (scRNA-seq) and subsequent functional testing.
- Use ECM proteomics to identify the key extracellular cues and paracrine signals regulating mesenchymal cell differentiation in regeneration.
Theme 4: Clinical translation by evaluation of therapies for vascular regeneration. PIs: Ascione, Mills (leads), Madeddu, Shah, Baker
1. To study the survival and efficacy of human vascular-targeted stem cell therapies in an advanced porcine model of acute MI at the Translational Biomedical Research Centre (Bristol) operating at NHS and GLPMA standards
Structure of the CVR
The Centre is fortunate to have the following collaborators:
Dr Mihaela Crisan, University of Edinburgh, Centre for Cardiovascular Science
Dr Andrea Caporali, University of Edinburgh, Centre for Cardiovascular Science
Dr Bijan Modarai, King's College London, Department of Vascular Surgery
Dr Divaka Perera, King's College London, Department of Cardiology
Dr Enrico Petretto, Imperial College London, Department of Medicine
Dr Fiona M. Watt, King's College London, Centre for Stem Cells & Regenerative Medicine
Dr Gabor Foldes, Imperial College London, National Heart & Lung Institute
Dr Gillian Gray, University of Edinburgh, Centre for Cardiovascular Science
Dr Graeme Birdsey, Imperial College London, National Heart & Lung Institute
Dr Igor Ulitsky, Weizmann Institute, Israel
Dr James Minchin, University of Edinburgh, Centre for Cardiovascular Science
Dr Tom Johnson, University of Bristol, Bristol Heart Institute
Professor Benjamin D. Simons, University of Cambridge, Department of Physics
Professor Dan Peer, Tel Aviv University Cancer Biology Research Center, Department of Cell Research & Immunology
Professor David Newby, University of Edinburgh, Centre for Cardiovascular Science
Professor Jo Mountford, Scottish National Blood Transfusion Service
Professor Johan Hyllner, Cell & Gene Therapy Catapult
Professor Jorge Ferrer, Imperial College London, Department of Medicine
Professor Rene Botnar, King's College London, Division of Imaging Sciences & Biomedical Engineering
Professor Stuart Forbes, University of Edinburgh, MRC Centre for Regenerative Medicine