title: Robo4 cooperates with CXCR4 to specify hematopoietic stem cell localization to bone marrow niches.
abstract: Specific bone marrow (BM) niches are critical for hematopoietic stem cell (HSC) function during both normal hematopoiesis and in stem cell transplantation therapy. We demonstrate that the guidance molecule Robo4 functions to specifically anchor HSCs to BM niches. Robo4-deficient HSCs displayed poor localization to BM niches and drastically reduced long-term reconstitution capability while retaining multilineage potential. Cxcr4, a critical regulator of HSC location, is upregulated in Robo4(-/-) HSCs to compensate for Robo4 loss. Robo4 deletion led to altered HSC mobilization efficiency, revealing that inhibition of both Cxcr4- and Robo4-mediated niche interactions are necessary for efficient HSC mobilization. Surprisingly, we found that WT HSCs express very low levels of Cxcr4 and respond poorly to Cxcr4 manipulation relative to other hematopoietic cells. We conclude that Robo4 cooperates with Cxcr4 to endow HSCs with competitive access to limited stem cell niches, and we propose Robo4 as a therapeutic target in HSC transplantation therapy.
authors.affiliation: Institute for the Biology of Stem Cells, University of California Santa Cruz, Santa Cruz, CA 95064, USA.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Smith-Berdan
authors.forename: Andrew
authors.initials: A
authors.lastname: Nguyen
authors.forename: Deena
authors.initials: D
authors.lastname: Hassanein
authors.forename: Matthew
authors.initials: M
authors.lastname: Zimmer
authors.forename: Fernando
authors.initials: F
authors.lastname: Ugarte
authors.forename: Jesús
authors.initials: J
authors.lastname: Ciriza
authors.forename: Dean
authors.initials: D
authors.lastname: Li
authors.forename: Marcos E
authors.initials: ME
authors.lastname: García-Ojeda
authors.forename: Lindsay
authors.initials: L
authors.lastname: Hinck
authors.forename: E Camilla
authors.initials: EC
authors.lastname: Forsberg
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism*; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D020297:Mice, Congenic; D008815:Mice, Inbred Strains; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D019718:Receptors, CXCR4 / Q000378:metabolism / Q000502:physiology*; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction; D055153:Stem Cell Niche
chemical_list: D009419:Nerve Tissue Proteins; D019718:Receptors, CXCR4; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic; C540792:Robo4 protein, mouse