Sphingosine-1-Phosphate Receptor-3 Supports Hematopoietic Stem and Progenitor Cell Residence Within the Bone Marrow Niche

Abstract

Hematopoietic stem and progenitor cells (HSPCs) egress from bone marrow during homeostasis and at increased rates during stress; however, the mechanisms regulating their trafficking remain incompletely understood. Here we describe a novel role for lipid receptor, sphingosine-1-phosphate receptor 3 (S1PR3), in HSPC residence within the bone marrow niche. HSPCs expressed increased levels of S1PR3 compared to differentiated bone marrow cells. Pharmacological antagonism or knockout of S1PR3 mobilized HSPCs into blood circulation, suggesting that S1PR3 influences niche localization. S1PR3 antagonism suppressed bone marrow and plasma SDF-1, enabling HSPCs to migrate towards S1P-rich plasma. Mobilization synergized with AMD3100-mediated antagonism of CXCR4, which tethers HSPCs in the niche, and recovered homing deficits of AMD3100-treated grafts. S1PR3 antagonism combined with AMD3100 improved re-engraftment and survival in lethally irradiated recipients. Our studies indicate that S1PR3 and CXCR4 signaling cooperate to maintain HSPCs within the niche under homeostasis. These results highlight an important role for S1PR3 in HSPC niche occupancy and trafficking that can be harnessed for both rapid clinical stem cell mobilization and re-engraftment strategies, as well as the opportunity to design novel therapeutics for control of recruitment, homing, and localization through bioactive lipid signaling.

Lipid Mediated Regulation of Adult Stem Cell Behavior

“…This lipid of the eicosanoid family binds to specific receptors at the surface of HSCs (Hoggatt et al, 2009) that mediate activation of the Wnt signaling pathway, which is important for HSC specification during development (Goessling et al, 2009) and for expansion of adult HSCs (Reya et al, 2003). In addition, HSCs also express receptors for the signaling lipid sphingosine-1-phosphate (S1P) that regulate localization within the bone marrow niche (Ogle et al, 2017).…”

Regulatory role of sphingosine kinase and sphingosine-1-phosphate receptor signaling in progenitor/stem cells

“…HSCs and downstream partially lineage-committed progenitor cell functions are tightly linked to their migratory properties, especially during fetal development[ 33 , 34 ]. Although the majority of postnatal and adult HSCs/progenitors stay in BM specialized niches or cavities[ 35 ], some of the HSCs/progenitors belong to a highly migratory subpopulation that recirculates between BM and blood[ 36 , 37 ]. Suggestively, the HSC/progenitor trafficking mechanism supports full occupancy of stem cell niches in all BM cavities[ 37 , 38 ].…”

“…Although the majority of postnatal and adult HSCs/progenitors stay in BM specialized niches or cavities[ 35 ], some of the HSCs/progenitors belong to a highly migratory subpopulation that recirculates between BM and blood[ 36 , 37 ]. Suggestively, the HSC/progenitor trafficking mechanism supports full occupancy of stem cell niches in all BM cavities[ 37 , 38 ]. HSC trafficking is directed by an S1P blood/lymph/tissue gradient that is mostly maintained by SphK/S1P receptor and S1P-degrading enzyme S1P lyase network[ 38 ].…”

“…S1P concentration in peripheral blood and lymph regulates HSC and lymphocyte egress from lymphoid organs[ 34 , 37 ]. HSCs and progenitors express S1P1 receptor(s) that can sense blood plasma S1P and direct stem cell migration[ 40 ].…”

Current Developments in Mobilization of Hematopoietic Stem and Progenitor Cells and Their Interaction with Niches in Bone Marrow

“…Inhibition or knockout of S1PR3 results in mobilization of HSPCs into blood circulation, whereby S1PR3 antagonism suppresses bone marrow and plasma CXCL12/SDF-1 concentrations [139]. On the other hand, S1PR3 antagonism increases AMD3100 induced mobilization, indicating a synergy between S1PR3 and CXCR4 pathways.…”