Abstract 1890: Depletion of Transplanted Pro-Angiogenic Cells by a Suicide Approach Discloses a Crucial Role of Sustained Incorporation for Cardiac Repair after Myocardial Infarction
Endothelial progenitor cells improve neovascularisation of ischemic tissue by a broad repertoire of potential mechanisms. While initial studies documented that the cells incorporate and differentiate to cardiovascular cells, other studies suggested that short-time paracrine mechanisms mediate the beneficial effects. The question remains to what extent a physical incorporation is contributing to the beneficial effects of cell therapy. Pro-angiogenic cells were cultivated from peripheral blood mononuclear cells under conditions favouring endothelial commitment (“early EPC”) and were transduced with a lentiviral vector encoding thymidine kinase (TK) under the control of constitutively active promoter. TK activates the pro-drug gancyclovir (GV) to induce toxicity in the target cell. Injection of cells in mice after acute myocardial infarction (MI) significantly improved left ventricular ejection fraction (EF) as assessed by MRI and echocardiography up to 4 weeks compared to control mice. However, depletion of the TK-expressing cells by GV treatment at 2 weeks after cell infusion was associated with deterioration of EF measured at 4 weeks (no cells:37 ± 5%;TK-cells:61 ± 5.6%,TK-cells + GV:43 ± 4.6%). Likewise, endsystolic volume was significantly reduced in mice injected with TK-cells but was increased by cell depletion with GV. Consistently, the increased capillary density in TK-cell-treated mice was significantly reduced by GV treatment (lectin+ area: TK-cells: 11 ± 2.0, TK-cells+GV: 6.8 ± 2.5, p < 0.05). In order to examine the contribution of lineage-committed cells after MI, we selectively depleted KDR-positive cells by expressing TK under the control of the KDR-promoter. Injection of gancyclovir after 2 weeks in KDR-TK-cell treated mice also resulted in a deterioration of the EF measured at 4 weeks, however, the effect was less pronounced compared to the depletion of all cells by using the constitutively active promoter.
Conclusion: Depletion of infused cells 2 weeks after MI induced a decline of EF and capillary density. These data document that infused cells are physically incorporated weeks after transplantation. The contribution of specific cell lineages to the maintenance of functional improvement warrants further investigations.