Sphingosine-1-phosphate receptor modulation improves neurogenesis and functional recovery after stroke.

Cerebral ischemia activates neural progenitors that participate in brain remodeling following acute injury. Sphingosine-1-phosphate receptor (S1PR) signaling governs cell proliferation and mobilization, yet its potential impact on neural progenitors and stroke recovery remains poorly understood. The goal of this study was to investigate the impact of S1PR modulation on post-stroke neurogenesis and functional recovery, using a S1PR modulator BAF312. Mice were subjected to 60 min middle cerebral artery occlusion (MCAO) and received BAF312 starting from day 3 after MCAO until the end of experiment. BAF312 facilitated motor function recovery in MCAO mice until day 14 after surgery. Flow cytometry analysis revealed that BAF312 treatment led to an increase of type A cells in subventricular zone (SVZ), but not other progenitor cell subsets in MCAO mice. We found an increase of BrdU incorporation in SVZ DCX+ cells from MCAO mice receiving BAF312 and augmented proliferation of DCX+ cells in cultured neurospheres isolated from SVZ tissues. Notably, a S1PR1 antagonist W146 abolished BAF312-induced increase of SVZ type A cells from MCAO mice and proliferation of DCX+ cells in cultured neurospheres. Additionally, the benefit of BAF312 to improve neurogenesis and stroke recovery remains in Rag2-/- mice lacking of T and B cells. Our results demonstrate that S1PR modulation improves neurogenesis and functional recovery following brain ischemia.