Abstract
Myocardial
infarction (MI) induces
death of cardiac muscle and replacement by a
non-contractile fibrotic scar,
which ultimately leads to
heart failure. Current treatments restore
blood flow and assist with cardiac workload but none are regenerative, and
clinical trials using stem-cell- based approaches have been disappointing.
We have
previously shown that the cardiac lymphatic system is activated
following MI and that further stimulation with the lymphatic endothelial
specific isoform of VEGF-C, VEGF-CC156S,
resolves the immune response and improves cardiac function. Whilst this study demonstrates the potential
of this approach, VEGF-CC156S is sub-optimal for clinical use.
The aim of OxStem
Cardio is to enhance the intrinsic regenerative potential of the infarcted
adult heart using small molecules. To achieve this, we have established a
plexus formation assay and sprouting assay using human lymphatic endothelial
cells (hLEC), to mimic lymphangiogenesis in vitro. We miniaturized
these cell-based assays in a 384 well-plate high-throughput format to be able
to screen libraries of compounds. Both
of our assays are based on phenotypic screens and we are using automated
imaging and post-hoc analyses to select, cluster and quantify hits. Molecules of
interest will be further characterised using in vivo phenotypic screens in zebrafish and progressed through
combined medicinal chemistry and preclinical models of adult cardiac injury.
