"Coordinating Hematopoietic Stem Cell Trafficking through Sphingosine-1-phosphate Receptor Signals"

Claire Segar - PhD candidate
Ed Botchwey, PhD - Advisor

Hematopoietic stem cells (HSCs) traffic from the bone marrow niche into peripheral blood and tissue compartments in response to injury and inflammation. Understanding the signaling mechanisms that govern this cell mobilization and homing is critical in the design of novel endogenous tissue engineering strategies. The bone marrow niche compartment is a complex and highly organized structure made up of multiple cell types, matrices, and soluble factors that maintain and control HSC fate in vivo. Lipid mediators such as sphingosine-1-phosphate (S1P) have recently become recognized for their essential roles in spatial guidance, signaling, and ability to modify the sensitivity to other chemokines and growth factors. Here, we investigate the role of S1P receptors in governing the trafficking of hematopoietic stem and progenitor cells. We demonstrate that pharmacological antagonism of S1P receptor 3 leads to the rapid and selective mobilization of HSCs into peripheral blood in mice. Additionally, signaling through S1P receptors within bone marrow stromal cell populations alters the gradient of stromal derived factor-1 (SDF-1) across the endothelium. In a mouse model of lethal irradiation, we show that mobilized cells are capable of long-term re-engraftment and multilineage differentiation. This work establishes a role for S1P receptors in facilitating the trafficking of hematopoietic cells through differential receptor expression, which can be harnessed to enhance stem cell mobilization and re-engraftment.