title: Notch Receptor-Ligand Engagement Maintains Hematopoietic Stem Cell Quiescence and Niche Retention.
abstract: Notch is long recognized as a signaling molecule important for stem cell self-renewal and fate determination. Here, we reveal a novel adhesive role of Notch-ligand engagement in hematopoietic stem and progenitor cells (HSPCs). Using mice with conditional loss of O-fucosylglycans on Notch EGF-like repeats important for the binding of Notch ligands, we report that HSPCs with faulty ligand binding ability display enhanced cycling accompanied by increased egress from the marrow, a phenotype mainly attributed to their reduced adhesion to Notch ligand-expressing stromal cells and osteoblastic cells and their altered occupation in osteoblastic niches. Adhesion to Notch ligand-bearing osteoblastic or stromal cells inhibits wild type but not O-fucosylglycan-deficient HSPC cycling, independent of RBP-JK -mediated canonical Notch signaling. Furthermore, Notch-ligand neutralizing antibodies induce RBP-JK -independent HSPC egress and enhanced HSPC mobilization. We, therefore, conclude that Notch receptor-ligand engagement controls HSPC quiescence and retention in the marrow niche that is dependent on O-fucosylglycans on Notch.
authors: Department of Pathology, Case Western Reserve University, Cleveland, Ohio, USA.
authors: Weihuan
authors: W
authors: Wang
authors: Department of Pathology, Case Western Reserve University, Cleveland, Ohio, USA.
authors: Shuiliang
authors: S
authors: Yu
authors: Department of Pathology, Case Western Reserve University, Cleveland, Ohio, USA.
authors: Grant
authors: G
authors: Zimmerman
authors: Department of Pathology, Case Western Reserve University, Cleveland, Ohio, USA.
authors: Yiwei
authors: Y
authors: Wang
authors: Department of Pediatrics, Case Western Reserve University, Cleveland, Ohio, USA.
authors: Jay
authors: J
authors: Myers
authors: Center for Regenerative Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA.|Harvard Stem Cell Institute, Cambridge, Massachusetts, USA.|Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts, USA.
authors: Vionnie W C
authors: VW
authors: Yu
authors: Department of Pathology, Case Western Reserve University, Cleveland, Ohio, USA.
authors: Dan
authors: D
authors: Huang
authors: Department of Pathology, Case Western Reserve University, Cleveland, Ohio, USA.
authors: Xiaoran
authors: X
authors: Huang
authors: Department of Pathology, Genentech, Inc., South San Francisco, California, USA.
authors: Jeongsup
authors: J
authors: Shim
authors: Department of Blood Transfusion, Affiliated Hospital of Luzhou Medical College, Luzhou, Sichuan Province, People's Republic of China.
authors: Yuanshuai
authors: Y
authors: Huang
authors: University School, Hunting Valley, Ohio, USA.
authors: William
authors: W
authors: Xin
authors: Department of Pathology, Case Western Reserve University, Cleveland, Ohio, USA.
authors: Peter
authors: P
authors: Qiao
authors: Department of Molecular Biology Oncology, Genentech, Inc., South San Francisco, California, USA.
authors: Minhong
authors: M
authors: Yan
authors: Department of Pathology, Case Western Reserve University, Cleveland, Ohio, USA.
authors: Wei
authors: W
authors: Xin
authors: Center for Regenerative Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA.|Harvard Stem Cell Institute, Cambridge, Massachusetts, USA.|Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts, USA.
authors: David T
authors: DT
authors: Scadden
authors: Department of Cell Biology, Albert Einstein College of Medicine, New York, New York, USA.
authors: Pamela
authors: P
authors: Stanley
authors: Department of Pathology, Genentech, Inc., South San Francisco, California, USA.
authors: John B
authors: JB
authors: Lowe
authors: Department of Pediatrics, Case Western Reserve University, Cleveland, Ohio, USA.
authors: Alex Y
authors: AY
authors: Huang
authors: Department of Molecular Biology Oncology, Genentech, Inc., South San Francisco, California, USA.
authors: Christian W
authors: CW
authors: Siebel
authors: Department of Pathology, Case Western Reserve University, Cleveland, Ohio, USA.
authors: Lan
authors: L
authors: Zhou
mesh_terms: D000818:Animals; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D006801:Humans; D051379:Mice; D051880:Receptors, Notch / Q000378:metabolism*; D015398:Signal Transduction; D055153:Stem Cell Niche / Q000235:genetics*; D017154:Stromal Cells / Q000378:metabolism*
chemical_list: D051880:Receptors, Notch
keywords: HSC egress and mobilization; HSC quiescence and niche retention; Notch receptor-ligand interactions; O-fucosylglycans on Notch