Clinical/Translational Research Sox2 Transduction Enhances Cardiovascular Repair Capacity of Blood-Derived Mesoangioblasts

Rationale: Complementation of pluripotency genes may improve adult stem cell functions. Objectives: Here we show that clonally expandable, telomerase expressing progenitor cells can be isolated from peripheral blood of children. The surface marker profile of the clonally expanded cells is distinct from hematopoietic or mesenchymal stromal cells, and resembles that of embryonic multipotent mesoangioblasts. Cell numbers and proliferative capacity correlated with donor age. Isolated circulating mesoangioblasts (cMABs) express the pluripo-tency markers Klf4, c-Myc, as well as low levels of Oct3/4, but lack Sox2. Therefore, we tested whether overexpression of Sox2 enhances pluripotency and facilitates differentiation of cMABs in cardiovascular lineages. S tem cell therapy is a potential therapeutic option for treating ischemic cardiovascular diseases. Several types of adult stem or progenitor cells have been shown to improve recovery after ischemic damage and contribute to vasculogen-esis and possibly cardiomyogenesis, bone marrow– derived cells being the most extensively studied to date. Overall, the clinical trials using bone marrow– derived cells for patients with acute or chronic ischemic heart disease demonstrated the safety of the procedure and generally documented improvements of heart function and clinical outcome. 1–5 However, the increase in contractile recovery was modest in most trials (for review see the recent metaanalysis of Lipinski et al 6). The modest effects of the transplanted cells have been attributed to rather low engraftment and survival as well as their limited cardiomyogenic capacity. 7,8 Additionally, increasing age and risk factors for coronary artery disease significantly reduce the functional activity of bone marrow– derived and circulating cells in patients. 9 –11 Aging is known to affect stem/progenitor cell function in animal models and may lead to exhaustion of the endogenous stem cell pools. 12 Therefore, we investigated whether subsets of circulating progenitor cells might exist during early human postnatal development and during childhood. In the circulating blood of adults, different subsets of hematopoietic progenitor cells, endothelial progenitor cells and-after mobilization-mesen-chymal stromal cells (MSCs) have already been described. 13–15 Here, we identified multipotent, clonally ex-pandable, telomerase-positive circulating cells in the blood of children, which are distinct from previously identified circulating hematopoietic and endothelial progenitor cells. The isolated cells can be induced to differentiate to the principle cell types of 3 cardiovascular lineages and form skeletal muscle. Phenotypically, the isolated cells resemble previously described vessel-associated mesoangioblasts. 16 The isolated cells express 3 of the 4 pluripotency genes 17 that have been shown to reprogram somatic cells to …