Abstract 3487: Sox2 Transduction Induces Pluripotency and Enhances Cardiovascular Repair Capacity of Blood-derived Mesoangioblasts
Expression of the 4 factors Oct3/4, Klf4, c-myc and Sox2 converts somatic cells into induced pluripotent cells. Human circulating mesoangioblasts (cMAB) have been recently identified in peripheral blood and were characterised by distinct marker expression compared to bone marrow-derived stem cells and endothelial progenitor cells. Mesoangioblasts are described as mesodermal progenitors. Indeed, single cell derived cMAB can differentiate to cardiovascular cells such as cardiomyocytes (CM), smooth muscle (SM) cells, and endothelial cells (EC). cMAB expressed the pluripotency genes Oct3/4, Klf4, and c-Myc at gene and protein level, whereas Sox2 was not expressed. Therefore, we hypothesized that Sox2 transduction may be sufficient to induce pluripotency. Lentiviral transduction of SOX2 in cMAB (Sox-MAB) enhanced the differentiation capacity of cMABs in EC (18-fold) and CM (73-fold) in vitro as evidenced by the expression of GFP under the control of the eNOS and αMHC promoter, respectively. Furthermore, the number of SM actin positive cells induced by TGFβ treatment was higher in Sox-MAB. In addition, the pluripotency of Sox-MAB was shown by demonstrating the generation of endodermal and ectodermal progenies by using established differentiation assays. Hepatocyte differentiation was confirmed by CK18 and α-fetoprotein expression, whereas neuronal differentiation resulted in the appearance of elongated cells expressing Nestin. In order to test whether Sox-MAB may exhibit improved therapeutic potential, we injected Sox-MAB into nude mice after acute myocardial infarction (AMI). Four weeks after cell therapy with Sox-MAB, cardiac function was significantly improved compared to mice treated with control cMAB. Furthermore, cell therapy with Sox-MAB resulted in increased number of α-sarcomeric actinin-, SM actin-, and von Willebrand factor-positive human cells compared to cell therapy with control cMAB as evidenced by immunostaining. Taken together, these data indicate that transduction of one single factor, Sox2, induced pluripotency in human cMAB. The complementation of Sox2 in Oct3/4-, Klf4-, and c-myc-expressing cMABs enhanced the differentiation into all three cardiovascular lineages and improved the functional recovery after AMI.