Phenotypic screening identifies kenpaullone as a prolymphangiogenic compound to improve heart repair following myocardial infarction

Current treatments restore blood flow and assist with cardiac workload but do not promote regeneration. We have previously shown endogenous growth of the cardiac lymphatic system following MI and further stimulation with the lymphatic endothelial specific mutated Vascular Endothelial Growth Factor-C (VEGF-C) isoform, VEGFC-C156S, resolves the immune response and improves cardiac function.

However, the short half-life of VEGFC-C156S makes it suboptimal for clinical use, highlighting the need for alternative prolymphangiogenic strategies. We established a spheroid-based sprouting assay using human lymphatic endothelial cells to mimic lymphangiogenesis and performed a phenotypic screen of focused libraries of epigenetic regulators, kinase inhibitors, and stem cell modulators. Automated imaging and quantitative analysis identified several kinase inhibitors, previously characterized as GSK3ß inhibitors, as prolymphangiogenic regulators.