Sphingosine-1-phosphate receptor 2 agonist mobilizes endogenous reparative Muse cells that facilitate damaged myocardial tissue repair in rabbit

Abstract Muse cells, SSEA-3(+) non-tumorigenic pluripotent stem cells, reside in the bone marrow (BM), peripheral blood and organ connective tissue as cells. Circulating Muse cells, either endogenous or exogenously administered, selectively accumulate to damaged tissue by sensing sphingosine-1-phosphate (S1P) produced by the damaged tissue, differentiate into tissue-constituent cells including vascular cells, replace apoptotic/damaged cells and repair the tissue. They are expandable to clinical scale and are applied to clinical trials. Acute myocardial infarction model (AMI) model rabbits were subcutaneously injected either with vehicle, S1PR2-agonist, or S1PR2-agonist + S1PR2-antagonist. The S1PR2-agonist group showed the statistically meaningful increase of the endogenous peripheral blood-Muse cell number at 12 h (both p < 0.05), reduction of the infarct size (p < 0.05) and improvement of the left ventricular function (p < 0.05) at 2 weeks compared with the other 2 groups. The increase in peripheral blood-Muse cells positively correlated with LV ejection fraction, and inversely correlated with infarct size in statistical analysis. Green fluorescent protein (GFP)-autologous BM-Muse cells were transplanted back into the BM of the same animal, AMI model was made 48 hrs after, and then vehicle or S1PR2 agonist was administered subcutaneously. At 2 weeks, the number of GFP-Muse cells positive for cardiac markers, troponin-I, α-actinin and connexin-43, and those positive for vascular marker CD31, was higher in the border areas in the S1PR2-agonist group compared with that in the vehicle group. Along with administration of exogenous stem cells, the efficient mobilization of endogenous stem cells such as S1PR2-agonist for Muse cells, might be an alternative promising therapeutic approach.