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).

References:

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.

  1. To identify the transcriptional and epigenetic pathways underlying the regenerative function of circulating progenitor cells (BOEC).
  2. To define endogenous EC pathways promoting neovascularisation and regeneration.
  3. To provide in vitro and in vivo functional validation of EC regeneration pathways.

Theme 2: Exogenous vascular regeneration PIs: Emanueli (lead) Baker, Henderson, Mayr.

  1. Investigate the therapeutic potential of established hESC-EC in rodent MI.
  2. Promote arterial and lymphatic specification of hESC-EC and assess the impact of transplanted hESC-AEC and -LEC on post-MI vascular regeneration.
  3. Investigate the contribution of EV to the therapeutic responses to hESC-ECs.
  4. 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.

  1. Investigate the functional phenotype of cardiac mesenchymal cell subpopulations in health and disease giving rise to vascular smooth muscle cells (VSMC) or fibroblasts.
  2. Identify and characterise the pro-reparative mesenchymal subpopulations post-MI using a single cell RNA sequencing approach (scRNA-seq) and subsequent functional testing.
  3. 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

CVR Management Group

Andrew Baker

Andrew H Baker, University of Edinburgh

Andrew H Baker, University of Edinburgh

Mairi Brittan

Mairi Brittan, University of Edinburgh

Mairi Brittan, University of Edinburgh

Paolo Madeddu

Paolo Madeddu, University of Bristol

Manuel Mayr

Manuel Mayr, King's College London

Nicholas L Mills

Nicholas L Mills, University of Edinburgh

Nicholas L Mills, University of Edinburgh