title: EphB4 Expressing Stromal Cells Exhibit an Enhanced Capacity for Hematopoietic Stem Cell Maintenance.
abstract: The tyrosine kinase receptor, EphB4, mediates cross-talk between stromal and hematopoietic populations during bone remodeling, fracture repair and arthritis, through its interactions with the ligand, ephrin-B2. This study demonstrated that transgenic EphB4 mice (EphB4 Tg), over-expressing EphB4 under the control of collagen type-1 promoter, exhibited higher frequencies of osteogenic cells and hematopoietic stem/progenitor cells (HSC), correlating with a higher frequency of long-term culture-initiating cells (LTC-IC), compared with wild type (WT) mice. EphB4 Tg stromal feeder layers displayed a greater capacity to support LTC-IC in vitro, where blocking EphB4/ephrin-B2 interactions decreased LTC-IC output. Similarly, short hairpin RNA-mediated EphB4 knockdown in human bone marrow stromal cells reduced their ability to support high ephrin-B2 expressing CD34(+) HSC in LTC-IC cultures. Notably, irradiated EphB4 Tg mouse recipients displayed enhanced bone marrow reconstitution capacity and enhanced homing efficiency of transplanted donor hematopoietic stem/progenitor cells relative to WT controls. Studies examining the expression of hematopoietic supportive factors produced by stromal cells indicated that CXCL12, Angiopoietin-1, IL-6, FLT-3 ligand, and osteopontin expression were more highly expressed in EphB4 Tg stromal cells compared with WT controls. These findings indicate that EphB4 facilitates stromal-mediated support of hematopoiesis, and constitute a novel component of the HSC niche.
authors.affiliation: Mesenchymal Stem Cell Laboratory, School of Medical Sciences, Faculty of Health Sciences, University of Adelaide, Adelaide, South Australia, Australia.|Centre for Stem Cell Research, University of Adelaide, Adelaide, South Australia, Australia.|School of Pharmacy and Medical Sciences and Sansom Institute, University of South Australia, Adelaide, South Australia, Australia.|Cancer Theme, South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia.
authors.forename: Thao M
authors.initials: TM
authors.lastname: Nguyen
authors.affiliation: Mesenchymal Stem Cell Laboratory, School of Medical Sciences, Faculty of Health Sciences, University of Adelaide, Adelaide, South Australia, Australia.|Cancer Theme, South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia.|Division of Haematology, SA Pathology, Adelaide, South Australia, Australia.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Arthur
authors.affiliation: Mesenchymal Stem Cell Laboratory, School of Medical Sciences, Faculty of Health Sciences, University of Adelaide, Adelaide, South Australia, Australia.
authors.forename: Romana
authors.initials: R
authors.lastname: Panagopoulos
authors.affiliation: Mesenchymal Stem Cell Laboratory, School of Medical Sciences, Faculty of Health Sciences, University of Adelaide, Adelaide, South Australia, Australia.
authors.forename: Sharon
authors.initials: S
authors.lastname: Paton
authors.affiliation: School of Pharmacy and Medical Sciences and Sansom Institute, University of South Australia, Adelaide, South Australia, Australia.
authors.forename: John D
authors.initials: JD
authors.lastname: Hayball
authors.affiliation: Centre for Stem Cell Research, University of Adelaide, Adelaide, South Australia, Australia.|Myeloma Research Laboratory, School of Medical Sciences, Faculty of Health Sciences, University of Adelaide, Adelaide, South Australia, Australia.|Cancer Theme, South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia.
authors.forename: Andrew C W
authors.initials: AC
authors.lastname: Zannettino
authors.affiliation: Stem Cell Regulation Unit, St Vincent's Institute of Medical Research and Department of Medicine, University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Louise E
authors.initials: LE
authors.lastname: Purton
authors.affiliation: Laboratory of Cell and Tissue Biology, School of Medicine, Keio University, Tokyo, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Matsuo
authors.affiliation: Mesenchymal Stem Cell Laboratory, School of Medical Sciences, Faculty of Health Sciences, University of Adelaide, Adelaide, South Australia, Australia.|Centre for Stem Cell Research, University of Adelaide, Adelaide, South Australia, Australia.|Cancer Theme, South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia.
authors.forename: Stan
authors.initials: S
authors.lastname: Gronthos
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002478:Cells, Cultured; D005786:Gene Expression Regulation; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D036224:Receptor, EphB4 / Q000096:biosynthesis* / Q000235:genetics; D017154:Stromal Cells / Q000378:metabolism
chemical_list: C086681:Ephb4 protein, mouse; D036224:Receptor, EphB4
keywords: Bone marrow stromal cells; EphB; Haematopoietic stem cells; Mesenchymal stem cells; ephrinB