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 I-phosphate (SIP) regulates critical functions of mesoangioblast cell biology. SIP 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, C-2-ceramide treatment, or statirosporine treatment, as assessed by cell counting, as well as histone-associated fragments and caspase-3 activity determinations. SIP acts both as an intracellular messenger and through specific membrane receptors. Reall-time polymerase chain reaction analysis revealed that mesoangioblasts express the SIP-specific receptor SIP, and, to a minor extent, SIP, and SIP,. By using SIP receptor subtype-specific agonists and antagonists, we found that the proliferative response to SIP was mediated mainly by SIP,. By contrast, the antiapoptotic effect did not implicate SIP receptors. These findings demonstrate an important role of SIP in mesoangioblast proliferation and survival and indicate that targeting modulation of SIT-dependent signaling pathways may be used to improve the efficiency of muscle repair by these cells.