Inverse Agonism of Sphingosine 1-Phosphate Receptor Three Mobilizes Hematopoietic Stem Cell With Long Term Engraftment Capability

The use of peripheral blood as an alternative to bone marrow for obtaining hematopoietic stem cells (HSC) has been successfully established. This noninvasive procedure presents several advantages such as elimination of pain and anesthesia during cell harvest. In order to enrich peripheral blood with stem cells they need to be pharmacologically mobilized with stem cell mobilizing agents. G-CSF is the gold standard but it is costly, time-consuming and does not always result in sufficient mobilization and engraftment. New strategies to mobilize sufficient numbers of HSC without impairing their functional capability would drastically improve the therapeutic use of peripheral blood stem cells. AMD3100, also known as plerixafor, is a CXCR4 antagonist that is being evaluated in conjunction with G-CSF to enhance stem cell mobilization. In this work we show that inverse agonism of sphingosine 1-phosphate receptor three (S1P 3 ) significantly mobilizes HSC from the bone marrow into peripheral blood without affecting their ability to engraft and repopulate blood cells. HSC pre-treatment with VPC01211, an S1P 1 agonist and S1P 3 antagonist abolished chemotaxis towards SDF-1 in transwell migration assays and resulted in a 33 0ecrease in engraftment onto marrow-derived stromal cells and a 47 0ecrease in engraftment when combined with AMD3100. AMD3100 was used with or without VPC01091 to mobilize stem cells in GFP+ C57Bl/6 mice. Equal volumes of peripheral blood were used to reconstitute host C57Bl/6 mice after lethal irradiation. By 56 days post transplantation, animals receiving grafts mobilized with both AMD3100 and VPC01091 had a 162 0ncrease in donor content in their blood and a 63 0ncrease in donor content in their bone marrow over AMD3100 alone.

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