Sphingosine 1-phosphate mediates proliferation and survival of mesoangioblasts

Mesoangioblasts are stem cells capable of differentiating in various mesodermal tissues and are presently regarded as suitable candidates for cell therapy of muscle degenerative diseases, as well as myocardial infarction. The enhancement of their proliferation and survival after injection in vivo could greatly improve their ability to repopulate damaged tissues. In this study, we show that the bioactive sphingolipid sphingosine 1-phosphate (S1P) regulates critical functions of mesoangioblast cell biology. S1P evoked a full mitogenic response in mesoangioblasts, measured by labeled thymidine incorporation and cell counting. Moreover, S1P strongly counteracted the apoptotic process triggered by stimuli as diverse as serum deprivation, C₂-ceramide treatment, or staurosporine treatment, as assessed by cell counting, as well as histone-associated fragments and caspase-3 activity determinations. S1P acts both as an intracellular messenger and through specific membrane receptors. Realtime polymerase chain reaction analysis revealed that mesoangioblasts express the S1P-specific receptor S1P₃ and, to a minor extent, S1P₁ and S1P₂. By using S1P receptor subtype-specific agonists and antagonists, we found that the proliferative response to S1P was mediated mainly by S1P₂. By contrast, the antiapoptotic effect did not implicate S1P receptors. These findings demonstrate an important role of S1P in mesoangioblast proliferation and survival and indicate that targeting modulation of S1P-dependent signaling pathways may be used to improve the efficiency of muscle repair by these cells.