title: Robo4 plays a role in bone marrow homing and mobilization, but is not essential in the long-term repopulating capacity of hematopoietic stem cells.
abstract: Roundabout (Robo) family proteins are immunoglobulin-type surface receptors critical for cellular migration and pathway finding of neuronal axons. We have previously shown that Robo4 was specifically expressed in hematopoietic stem and progenitor cells and its high expression correlated with long-term repopulating (LTR) capacity. To reveal the physiological role of Robo4 in hematopoiesis, we examined the effects of Robo4 disruption on the function of hematopoietic stem cells (HSCs) and progenitors. In Robo4-deficient mice, basic hematological parameters including complete blood cell count and differentiation profile were not affected. In contrast to the previous report, HSC/hematopoietic progenitor (HPC) frequencies in the bone marrow (BM) were perfectly normal in Robo4(-/-) mice. Moreover, Robo4(-/-) HSCs were equally competitive as wild-type HSCs in transplantation assays and had normal long-term repopulating (LTR) capacity. Of note, the initial engraftment at 4-weeks after transplantation was slightly impaired by Robo4 ablation, suggesting a marginal defect in BM homing of Robo4(-/-) HSCs. In fact, homing efficiencies of HSCs/HPCs to the BM was significantly impaired in Robo4-deficient mice. On the other hand, granulocyte-colony stimulating factor-induced peripheral mobilization of HSCs was also impaired by Robo4 disruption. Lastly, marrow recovery from myelosuppressive stress was equally efficient in WT- and Robo4-mutant mice. These results clearly indicate that Robo4 plays a role in HSC trafficking such as BM homing and peripheral mobilization, but is not essential in the LTR and self-renewal capacity of HSCs.
authors.affiliation: Division of Cellular Therapy, Advanced Clinical Research Center, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Goto-Koshino
authors.forename: Yumi
authors.initials: Y
authors.lastname: Fukuchi
authors.forename: Fumi
authors.initials: F
authors.lastname: Shibata
authors.forename: Daichi
authors.initials: D
authors.lastname: Abe
authors.forename: Kana
authors.initials: K
authors.lastname: Kuroda
authors.forename: Shinichiro
authors.initials: S
authors.lastname: Okamoto
authors.forename: Toshio
authors.initials: T
authors.lastname: Kitamura
authors.forename: Hideaki
authors.initials: H
authors.lastname: Nakajima
mesh_terms: D000818:Animals; D001772:Blood Cell Count; D001854:Bone Marrow Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology; D006410:Hematopoiesis / Q000187:drug effects; D019650:Hematopoietic Stem Cell Mobilization; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic / Q000378:metabolism*
chemical_list: D009419:Nerve Tissue Proteins; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic; C540792:Robo4 protein, mouse; D016179:Granulocyte Colony-Stimulating Factor