title: Junctional Adhesion Molecule-A Is Highly Expressed on Human Hematopoietic Repopulating Cells and Associates with the Key Hematopoietic Chemokine Receptor CXCR4.
abstract: Hematopoietic stem/progenitor cells (HSPCs) reside in specialized bone marrow microenvironmental niches, with vascular elements (endothelial/mesenchymal stromal cells) and CXCR4-CXCL12 interactions playing particularly important roles for HSPC entry, retention, and maintenance. The functional effects of CXCL12 are dependent on its local concentration and rely on complex HSPC-niche interactions. Two Junctional Adhesion Molecule family proteins, Junctional Adhesion Molecule-B (JAM)-B and JAM-C, are reported to mediate HSPC-stromal cell interactions, which in turn regulate CXCL12 production by mesenchymal stromal cells (MSCs). Here, we demonstrate that another JAM family member, JAM-A, is most highly expressed on human hematopoietic stem cells with in vivo repopulating activity (p < .01 for JAM-A(high) compared to JAM-A(Int or Low) cord blood CD34(+) cells). JAM-A blockade, silencing, and overexpression show that JAM-A contributes significantly (p < .05) to the adhesion of human HSPCs to IL-1β activated human bone marrow sinusoidal endothelium. Further studies highlight a novel association of JAM-A with CXCR4, with these molecules moving to the leading edge of the cell upon presentation with CXCL12 (p < .05 compared to no CXCL12). Therefore, we hypothesize that JAM family members differentially regulate CXCR4 function and CXCL12 secretion in the bone marrow niche. Stem Cells 2016;34:1664-1678.
authors: Nuffield Division of Clinical Laboratory Medicine, Radcliffe Department of Medicine, Stem Cell Research, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom.|Radcliffe Department of Medicine, Stem Cell Research, NHS Blood and Transplant, John Radcliffe Hospital, Oxford, United Kingdom.
authors: Chao-Hui
authors: CH
authors: Chang
authors: Nuffield Division of Clinical Laboratory Medicine, Radcliffe Department of Medicine, Stem Cell Research, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom.|Radcliffe Department of Medicine, Stem Cell Research, NHS Blood and Transplant, John Radcliffe Hospital, Oxford, United Kingdom.
authors: Sarah J
authors: SJ
authors: Hale
authors: Bristol Institute for Transfusion Sciences, NHS Blood and Transplant, Bristol, United Kingdom.|Cancer Research School of Cellular and Molecular Medicine, University of Bristol, Bristol, United Kingdom.
authors: Charlotte V
authors: CV
authors: Cox
authors: Bristol Institute for Transfusion Sciences, NHS Blood and Transplant, Bristol, United Kingdom.|Cancer Research School of Cellular and Molecular Medicine, University of Bristol, Bristol, United Kingdom.
authors: Allison
authors: A
authors: Blair
authors: Nuffield Division of Clinical Laboratory Medicine, Radcliffe Department of Medicine, Stem Cell Research, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom.|Radcliffe Department of Medicine, Stem Cell Research, NHS Blood and Transplant, John Radcliffe Hospital, Oxford, United Kingdom.
authors: Barbara
authors: B
authors: Kronsteiner
authors: Nuffield Division of Clinical Laboratory Medicine, Radcliffe Department of Medicine, Stem Cell Research, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom.|Radcliffe Department of Medicine, Stem Cell Research, NHS Blood and Transplant, John Radcliffe Hospital, Oxford, United Kingdom.
authors: Rita
authors: R
authors: Grabowska
authors: Nuffield Division of Clinical Laboratory Medicine, Radcliffe Department of Medicine, Stem Cell Research, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom.|Radcliffe Department of Medicine, Stem Cell Research, NHS Blood and Transplant, John Radcliffe Hospital, Oxford, United Kingdom.
authors: Youyi
authors: Y
authors: Zhang
authors: Nuffield Division of Clinical Laboratory Medicine, Radcliffe Department of Medicine, Stem Cell Research, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom.|Radcliffe Department of Medicine, Stem Cell Research, NHS Blood and Transplant, John Radcliffe Hospital, Oxford, United Kingdom.
authors: David
authors: D
authors: Cook
authors: Nuffield Division of Clinical Laboratory Medicine, Radcliffe Department of Medicine, Stem Cell Research, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom.|Radcliffe Department of Medicine, Stem Cell Research, NHS Blood and Transplant, John Radcliffe Hospital, Oxford, United Kingdom.
authors: Cheen P
authors: CP
authors: Khoo
authors: Nuffield Division of Clinical Laboratory Medicine, Radcliffe Department of Medicine, Stem Cell Research, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom.|Radcliffe Department of Medicine, Stem Cell Research, NHS Blood and Transplant, John Radcliffe Hospital, Oxford, United Kingdom.
authors: Jack B
authors: JB
authors: Schrader
authors: Nuffield Division of Clinical Laboratory Medicine, Radcliffe Department of Medicine, Stem Cell Research, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom.|Radcliffe Department of Medicine, Stem Cell Research, NHS Blood and Transplant, John Radcliffe Hospital, Oxford, United Kingdom.
authors: Suranahi Buglass
authors: SB
authors: Kabuga
authors: Nuffield Division of Clinical Laboratory Medicine, Radcliffe Department of Medicine, Stem Cell Research, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom.|Radcliffe Department of Medicine, Stem Cell Research, NHS Blood and Transplant, John Radcliffe Hospital, Oxford, United Kingdom.
authors: Enca
authors: E
authors: Martin-Rendon
authors: Nuffield Division of Clinical Laboratory Medicine, Radcliffe Department of Medicine, Stem Cell Research, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom.|Radcliffe Department of Medicine, Stem Cell Research, NHS Blood and Transplant, John Radcliffe Hospital, Oxford, United Kingdom.
authors: Suzanne M
authors: SM
authors: Watt
mesh_terms: D000071916:AC133 Antigen / Q000378:metabolism; D018952:Antigens, CD34 / Q000378:metabolism; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D002448:Cell Adhesion / Q000187:drug effects; D054377:Chemokine CXCL12 / Q000494:pharmacology; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005312:Fetal Blood / Q000166:cytology; D055785:Gene Knockdown Techniques; D018922:HL-60 Cells; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D062745:Junctional Adhesion Molecule A / Q000378:metabolism*; D019169:Jurkat Cells; D011485:Protein Binding / Q000187:drug effects; D019718:Receptors, CXCR4 / Q000378:metabolism*; D055153:Stem Cell Niche / Q000187:drug effects
chemical_list: D000071916:AC133 Antigen; D018952:Antigens, CD34; C527276:CXCR4 protein, human; D054377:Chemokine CXCL12; D062745:Junctional Adhesion Molecule A; D019718:Receptors, CXCR4
keywords: CXCL12; CXCR4; Hematopoietic stem/progenitor cells; JAM-A; NSG transplants; Vascular niche