Abstract
E-selectin expressed in the bone marrow vasculature induces HSC proliferation.
Major finding: E-selectin expressed in the bone marrow vasculature induces HSC proliferation.
Clinical relevance: E-selectin blockade enhances HSC survival and recovery after chemotherapy or irradiation.
Impact: The vascular HSC niche plays an important role in modulating HSC quiescence and self-renewal.
The self-renewal potential of hematopoietic stem cells (HSC) is regulated by local microenvironmental signals provided by 2 anatomic niches within the bone marrow, the osteoblastic niche and the vascular niche. However, the relative contributions of each niche and the specific factors that modulate HSC behavior have not been fully characterized. Winkler and colleagues assessed the role of endothelial selectin (E-selectin), a cell adhesion molecule expressed by bone marrow endothelial cells in the vascular niche, in modulating HSC cell fate. HSC turnover was significantly decreased in mice deficient for Sele, the gene encoding E-selectin, and in wild-type mice treated with GMI-1070, a synthetic E-selectin antagonist. This reduction in HSC cycling was associated with an increased frequency of quiescent HSCs with greater self-renewal potential in bone marrow reconstitution assays and was specific to ablation of E-selectin but not the related protein platelet selectin (P-selectin), indicating that E-selectin negatively regulates stem-cell potential by stimulating HSC proliferation. This effect was mediated by stromal Sele expression in the bone marrow vasculature, particularly in the regenerating bone marrow after irradiation, and by noncanonical E-selectin ligands, possibly glycosphingolipid ligands expressed on HSCs. Intriguingly, Sele-deficient mice exhibited enhanced HSC survival and faster blood leukocyte recovery after treatment with cytotoxic chemotherapeutic agents, resulting in prolonged survival of these mice and suggesting that E-selectin loss promotes HSC chemoresistance. In a similar manner, transient pretreatment of wild-type mice with GMI-1070 conferred resistance to cytotoxic chemotherapy and augmented HSC self-renewal and survival in serial transplantation assays. These results identify a critical role for the vascular niche in inducing HSC proliferation and suggest that E-selectin inhibition may protect HSCs from the damaging bone-marrow–suppressive effects of chemotherapy and irradiation.
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