title: Vascular niche E-selectin regulates hematopoietic stem cell dormancy, self renewal and chemoresistance.
abstract: The microenvironment, or niche, surrounding a stem cell largely governs its cellular fate. Two anatomical niches for hematopoietic stem cells (HSCs) have been reported in the bone marrow, but a distinct function for each of these niches remains unclear. Here we report a new role for the adhesion molecule E-selectin expressed exclusively by bone marrow endothelial cells in the vascular HSC niche. HSC quiescence was enhanced and self-renewal potential was increased in E-selectin knockout (Sele(-/-)) mice or after administration of an E-selectin antagonist, demonstrating that E-selectin promotes HSC proliferation and is a crucial component of the vascular niche. These effects are not mediated by canonical E-selectin ligands. Deletion or blockade of E-selectin enhances HSC survival threefold to sixfold after treatment of mice with chemotherapeutic agents or irradiation and accelerates blood neutrophil recovery. As bone marrow suppression is a severe side effect of high-dose chemotherapy, transient blockade of E-selectin is potentially a promising treatment for the protection of HSCs during chemotherapy or irradiation.
authors.affiliation: Stem Cells and Cancer Group, Mater Medical Research Institute, South Brisbane, Queensland, Australia. iwinkler@mmri.mater.org.au
authors.forename: Ingrid G
authors.initials: IG
authors.lastname: Winkler
authors.forename: Valérie
authors.initials: V
authors.lastname: Barbier
authors.forename: Bianca
authors.initials: B
authors.lastname: Nowlan
authors.forename: Rebecca N
authors.initials: RN
authors.lastname: Jacobsen
authors.forename: Catherine E
authors.initials: CE
authors.lastname: Forristal
authors.forename: John T
authors.initials: JT
authors.lastname: Patton
authors.forename: John L
authors.initials: JL
authors.lastname: Magnani
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Lévesque
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000378:metabolism; D002454:Cell Differentiation; D019070:Cell Lineage / Q000187:drug effects / Q000528:radiation effects; D049109:Cell Proliferation / Q000187:drug effects / Q000528:radiation effects; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D019040:E-Selectin / Q000235:genetics / Q000378:metabolism; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects / Q000528:radiation effects; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000378:metabolism; D006918:Hydroxyurea / Q000494:pharmacology; D008024:Ligands; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D011827:Radiation
chemical_list: D019040:E-Selectin; D008024:Ligands; D006918:Hydroxyurea