Edinburgh-led British Heart Foundation Centre for Vascular Regeneration

Edinburgh-led British Heart Foundation Centre for Vascular Regeneration

Working together to repair damaged hearts

The Edinburgh-led British Heart Foundation Centre for Vascular Regeneration (CVR), headed up by Professor Andrew Baker, is a collaboration between the University of Edinburgh, the University of Bristol, Imperial College London and King’s College London. The Centre is funded from 2017 – 2021 by the British Heart Foundation’s Mending Broken Hearts campaign.

Our vision is to integrate innovative cardiovascular research with a truly translational and clinically-focused programme of work, designed to identify, develop and test effective approaches to vascular regeneration in the post-myocardial infarction setting.”

Professor Andrew Baker, Centre Lead

The British Heart Foundation also funded the first phase of the Centre, a collaboration between Edinburgh, Bristol and King’s, from 2013 – 2017.

The current research is carried out by a multidisciplinary team, comprising cardiologists, cardiac surgeons and basic scientists with expertise in regenerative medicine and vascular biology.

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 (co-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

Contact us

Address: Centre for Cardiovascular Sciences, Queen’s Medical Research Institute, 47 Little France Crescent, Edinburgh, EH16 4TJ

Research-specific enquires can be directed to the relevant Principal Investigator. 

 

Cross-centre collaboration

The British Heart Foundation also funds an Oxbridge-led Centre for Regenerative Medicine and an Imperial-led Cardiovascular Regenerative Medicine Centre.

A joint symposium of the 3 Centres of Regenerative Medicine is held annually, enabling cross-centre collaboration.

 

 

Cross Centre Activities

As part of its Mending Broken Hearts campaign, the British Heart Foundation funds 3 Centres:

  • Edinburgh-led Centre for Vascular Regeneration, directed by Professor Andrew Baker
  • Imperial-led Cardiovascular Regenerative Medicine Centre, directed by Professor Sian Harding
  • Oxbridge-led Centre for Regenerative Medicine, directed by Professor Paul Riley

 

 

People

The Principal Investigators, Post Doctorates, and Collaborators who are part of the the Edinburgh-led Centre for Vascular Regeneration. 

Theme 1 - Endogenous vascular regeneration: Assessing mechanisms to activate endogenous vascular regeneration

Vascular endothelial cells play a crucial role in cardiac regeneration, through promoting blood vessel growth and providing morphogenic signals to cardiomyocytes. Both circulating and vessel wall resident endothelial progenitor cells have been implicated in angiogenesis. We are focusing on circulating and resident endothelial pathways to understand the mechanisms driving vascular regeneration.

Theme 2 - Exogenous vascular regeneration: Developing exogenous sources of vascular regeneration

Theme 2 is developing proangiogenic cellular products starting from human (h) pluripotent stem cells (SC): prevalently embryonic stem cells (ESC), but also induced pluripotent stem cells (iPSC). We develop new RNA biology knowledge and apply it to improve the process of endothelial differentiation of SC. We are also expanding the understanding of extracellular vesicles, especially exosomes, released by SCs and their importance in modulating the paracrine activity of the cells. Exosomes represent a promising option for acellular regenerative medicine.

Vascular smooth muscle cells derived from human cardiac pericytes. In green, Calponin. In red, alpha-Smooth muscle actin.

Theme 3 - Targeting cardiac mesenchyme: Targeting cellular pathways and matrix interactions to drive vascular repair and regeneration

We are using a multidisciplinary approach to identify and characterise the role of mesenchymal cell subpopulations involved in cardiovascular repair, with the ultimate goal of therapeutically targeting and modulating post-myocardial infarction remodelling and repair via cell-based or drug-able approaches.

Theme 4 - Clinical translation: Evaluating clinically-relevant GMP-compatible human cell types in an advanced porcine model of closed chest balloon MI with immunosuppression

Under Theme 4 we will test in an advanced porcine model of MI the three human cell types developed by our scientists including BOECs cells, CD16+CD56- pro-angiogenic monocytes and pericytes. Translation of these cell-based treatments to bed side require the testing of their safety and efficacy in advanced experimental models operated by clinical experts at NHS and GLP standards and highly relevant to human. To be meaningful, these evaluations need to be based on the same quality of in-vivo imaging used in the NHS. In Theme 4 of our Centre, we are using this rigorous preclinical testbed approach taking advantage of the BHF and MRC co-funded Translational Biomedical Research Centre (TBRC) at the University of Bristol.