Theme 3 - Targeting cardiac mesenchyme

Targeting cellular pathways and matrix interactions to drive vascular repair and regeneration

Hallmarks of the post-myocardial infarction response include scar formation, collagen deposition (interstitial and perivascular fibrosis) and neovascularisation (capillary and arteriole formation and collateralisation). In addition, mesenchymal cells influence post-myocardial infarction remodelling through paracrine interactions with other cardiac cells. These phenomena are pivotal to the clinical outcomes of myocardial infarction patients. However, the structural and functional heterogeneity of the cardiac mesenchyme in response to risk factors (such as diabetes) and the local environment (reperfusion injury/oxidative stress) and how this shapes the fibrotic/arteriogenic response to myocardial infarction is still unclear.

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.

Our aims are to:

  1. Investigate the functional phenotype of cardiac mesenchymal cell subpopulations in health and disease giving rise to vascular smoot muscle cells or fibroblasts.
  2. Identify and characterise the pro-reparative mesenchymal subpopulations post-myocardial infarction using a single cell RNA sequencing approach and subsequent functional testing.
  3. Use ECM proteomics to identify the key extracellular cues and paracrine signals regulating mesenchymal cell differentiation in regeneration.

Principal investigators

Neil Henderson, Paolo Madeddu (Leads), Manuel Mayr, Ajay Shah