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Abstract 362: Deletion of Gata4 and Gata6 in the c-Kit Lineage Augments Cellular Fusion in vivo

Cell therapy for treatment of ischemic heart disease has been under rigorous evaluation in recent years. Heart-derived c-Kit cells showed promising results in clinical trials with scar reduction and improved ejection fraction following coronary infusion. We previously developed a c-Kit lineage tracing model showing that these cells very rarely convert into de novo cardiomyocytes. To potentially reduce this rate to zero, and unequivocally evaluate cellular fusion processes in vivo, we deleted the cardiogenic transcription factors Gata4 and Gata6 in c-Kit cells using a Cre-loxP approach (Kit-Gata4/6 KO). We used the tamoxifen inducible Kit-MerCreMer allele crossed into Gata4/6 homozygous LoxP targeted background and the Rosa26-eGFP reporter, which were given tamoxifen at weaning to delete Gata4 and Gata6 in all c-Kit expressing cells and show them and their progeny as eGFP positive. Unexpectedly, we observed a greater than 10-fold increase in Kit lineage-traced cardiomyocytes in some Kit-Gata4/6 KO mice compared to Kit only controls with up to 4 months of treatment. Exploration of other tissues revealed a dramatic increase in presumed Kit-lineage traced skeletal muscle fibers in Kit-Gata4/6 KO mice as well. However, investigation of this effect suggested that this increase in presumed Kit-lineage traced cardiomyocytes and skeletal muscle fibers was due to an alteration in the immune cell compartment of these mice that generated greater rates of fusion. Indeed, analysis of Kit-derived hematopoietic lineages present in the heart showed a 6-fold increase in leukocyte infiltration (CD45 + ) and a 60-fold increase in dendritic cells (CD11c + ) from Kit-Gata4/6 KO mice. Kit-eGFP + bone marrow was also transplanted into mice expressing a membrane tomato reporter. Kit-Gata4/6 KO bone marrow showed a 3-fold increase in Kit-eGFP cells, although all these myocytes had the membrane tomato tag indicting that these events were all due to fusion. Hence, alterations in c-Kit cell activity likely impacts the activity of the immune system and the fusigenic activity of derived cells.