TRANSPLANTATION OF EXPANDED BONE MARROW-DERIVED VERY SMALL EMBRYONIC-LIKE STEM CELLS (VSEL-SCs) IMPROVES LEFT VENTRICULAR FUNCTION AND REMODELING AFTER MYOCARDIAL INFARCTION

Adult bone marrow-derived very small embryonic-like stem cells (VSEL-SCs) exhibit a Sca-1+/ Lin-/CD45phenotype and can differentiate into various cell types, including cardiomyocytes and endothelial cells. We have previously reported that transplantation of a small number (1×106) of freshly isolated, non-expanded VSEL-SCs into infarcted mouse hearts resulted in improved left ventricular (LV) function and anatomy. Clinical translation, however, will require large numbers of cells. Because the frequency of VSEL-SCs in the marrow is very low, we examined whether VSEL-SCs can be expanded in culture without loss of therapeutic efficacy. Mice underwent a 30min coronary occlusion followed by reperfusion and, 48 h later, received an intramyocardial injection of vehicle (group I, n=11), 1×105 EGFP-labeled expanded untreated VSEL-SCs (group II, n=7), or 1×105 EGFP-labeled expanded VSEL-SCs preincubated in a cardiogenic medium (group III, n=8). At 35 d after MI, mice treated with preincubated VSEL-SCs exhibited better global and regional LV systolic function and less LV hypertrophy compared with vehicle-treated controls. In contrast, transplantation of expanded but untreated VSEL-SCs did not produce appreciable reparative benefits. Scattered EGFP+ cells expressing α-sarcomeric actin, PECAM-1, or von Willebrand factor were present in VSEL-SC-treated mice, but their numbers were very small. No tumor formation was observed. We conclude that VSEL-SCs expanded in culture retain the ability to alleviate LV dysfunction and remodeling after a reperfused MI provided that they are exposed to a combination of cardiomyogenic growth factors and cytokines prior to transplantation. Counter intuitively, the mechanism whereby such preincubation confers therapeutic efficacy does not involve differentiation into new cardiac cells. These results support the potential therapeutic utility of VSEL-SCs for cardiac repair. Address for correspondence: Buddhadeb Dawn, M.D., Division of Cardiovascular Diseases, 3901 Rainbow Blvd, Rm. 1001, Eaton Hall, Kansas City, KS 66160, Tel: (913) 588-6015, Fax: (913) 588-6010, [email protected] Or Roberto Bolli, M.D., Division of Cardiovascular Medicine, 550 S. Jackson St., ACB, 3rd Floor, Louisville, KY 40292, Tel: (502) 852-1837, Fax: (502) 852-6474, [email protected]. Conflict of interest: None NIH Public Access