Abstract 3421: Sox2 Converts Human Mesoangioblasts into Nanog-Expressing Multipotent Cells with Enhanced Cardiac Repair
Induced pluripotent cells (iPS) were generated by overexpression of four factors (Oct3/4, Klf4, c-myc and Sox2) in fibroblasts and showed similar characteristic as embryonic stem (ES) cells. In contrast to iPS and ES cells, adult stem cells have a reduced plasticity. Therefore, we investigated whether reconstitution of the four pluripotency genes in adult progenitor cells improves their therapeutic capacity. Circulating mesoangioblasts (cMAB) have been recently identified in peripheral blood and showed distinct marker expression to bone marrow-derived stem cells and endothelial progenitor cells. cMAB are clonally expandable and exhibit high telomerase activity. cMAB expressed the pluripotency genes Oct3/4, KLF4, and c-Myc, whereas Sox2 and another important stemness gene, Nanog was not expressed. Since only Sox2 was absent out of the four pluripotency genes, we hypothesized that Sox2 transduction may be sufficient to induce pluripotency. Sox2 was overexpressed by lentiviral vector. Interestingly, Sox2-tranduced cMAB not only express Sox2 but also re-express the stem cell gene Nanog. Controls confirmed that the constitutively expressed genes, Oct3/4, KLF4, and c-myc, remained present after Sox2 transduction. Sox2-transduced cMAB formed embryoid body-like structures in culture. In order to test whether Sox2-transduced cells may exhibit improved therapeutic potential, we injected Sox2-transduced cMABs into nude mice after acute myocardial infarction. Four weeks after cell therapy with Sox-overexpressing cells, cardiac function was improved compared to mice treated with control cells (LVEDV/weight; 1.34 ± 0.14 vs 1.88 ± 0.02 μl/g, LVEDP; 13.2 ± 1.0 vs 18.7 ± 2.6 mmHg, dp/dt max; 7989 ± 1030 vs 6331 ± 149 mmHg/s, dp/dt min; 6583 ± 683 vs 4792 ± 514 mmHg/s, and Tau; 9.2 ± 0.8 vs 11.6 ± 1.8 ms, respectively). In summary, the complementation of Sox2 in Oct3/4-, Klf4-, and c-myc-expressing cMABs induced Nanog expression and improved the cardiac regeneration capacity of these circulating adult stem cells.