S1P and C1P # novel regulators of stem cell trafficking

There is accumulating evidence that levels of the stromal-derived factor-1 (SDF-1) level in peripheral blood does not consistently correlate with mobilization of hematopoietic stem/progenitor cells (HSPCs) and that SDF-1 does not play an exclusive role in the homing of HSPCs into bone marrow (BM), implying the existence of additional factors. Our new data identify a potentially important role for sphingosine-1-phosphate (S1P) in the trafficking of HSPCs. Mice deficient in S1P kinase or animals with S1P receptor type 1 knockout (S1P1-/-) are poor mobilizers. Similarly, blockade of S1P1 by a small-molecule antagonist impairs homing and engraftment of HSPCs after transplantation. We have also reported that S1P released from hemolyzed erythrocytes could be involved in the pathogenesis of paroxysmal nocturnal hemoglobinuria (PNH) by increasing overall motility and giving an expansion advantage to PNH-affected, glycosylphosphatidylinositol (GPI-A)-deficient HSPCs. In addition, we have also discovered that another bioactive lipid, ceramide-1-phosphate (C1P), like S1P, strongly chemoattracts HSPCs. Based on these data, our central hypothesis is that the bioactive lipids S1P and C1P play an important and presently underappreciated role in the trafficking of HSPCs. Our approach will exploit small molecule- and genetics-based strategies in mouse models to characterize, from a mechanistic point of view, the involvement of S1P and C1P in stem cell trafficking which we hope will lead to development of improved strategies for clinical HSPC mobilization and engraftment. Aim 1. To define the mechanisms by which Sphingosine-1-phosphate regulates HSPC mobilization and homing. Aim 2. To test the hypothesis that S1P-induced hypermotility of GPI-A-deficient HSPCs is central to the pathogenesis of PNH. Aim 3. To test the hypothesis that Ceramide-1-phosphate (C1P) is a novel regulator of HSPC trafficking.