Abstract 1740: Lnk Gene Deficiency Contributes to Cardiac Repair post Myocardial Infarction by Enhancing Regenerative Capacity of Bone Marrow-derived Endothelial Progenitor Cells and Resident Cardiac Stem Cells
Background: Lnk is a negative regulator of self-renewality of hematopoietic stem cells. However, effect of Lnk on kinetics of endothelial progenitor cells (EPCs) and cardiac progenitor cells (CPCs) for cardiac repair post myocardial infarction (MI) is unknown.
Methods and Results: MI was induced by ligating left anterior descending arteries of wild type (WT) and Lnk −/− (KO) mice. Real-time PCR confirmed the expression of Lnk gene in bone marrow (BM) and heart of WT, but not KO mice. Necropsy examination 28 days post MI disclosed augmentation of capillary density (WT, 713 ± 28; KO, 937 ± 157/mm2, P < 0.01) and inhibition of LV fibrosis (WT, 15.2 ± 4.3; KO, 8.0 ± 5.0%. P < 0.05) in KO than WT. Echocardiography at day 28 revealed preservation of LV function in KO than WT (Fractional shortening: WT, 17.7 ± 2.6; KO, 29.2 ± 5.6%; Regional wall motion score: WT, 25.4 ± 3.4; KO, 19.9 ± 0.9, P < 0.01). The percentage of c-kit+/Sca-1+/lin- cells (KSL) in BM at day 7 and the number of circulating Sca-1+/lin- cells (SL) at day 14 increased in KO compared with WT (KSL: WT, 7.1 ± 0.1; KO, 16.3 ± 0.3%; SL: WT, 23.5 ± 3.7x104; KO, 56.0 ± 12.4 x104 cells/ml, P < 0.05). The number of CPCs (c-kit+/GATA4+ cells) in the infarcted myocardium was greater in KO than WT (WT, 0.8 ± 0.4; KO, 1.5 ± 0.4 cells/mm2, PWT) and KO mice receiving WT BM (WT-> KO) compared with WT receiving WT BM (WT-> WT) (double positive cell: WT-> WT, 87 ± 75; WT->KO, 350 ± 39; KO-> WT, 532 ± 119; KO-> KO: 647 ± 175 cells/mm2, P < 0.05). Dual labeling for GFP and GATA4 also demonstrated the equivalent increase in resident CPCs (GFP-/GATA4+ cells) in KO-> WT and WT- > KO than WT- > WT.
Conclusions: Lnk−/− mice demonstrated enhanced cardiac repair through augmenting the kinetics of BM-derived EPCs and resident CPCs. Lnk gene deletion targeting stem/progenitor cells in both BM and heart may be a promising strategy for cardiac regeneration post MI.