Notch receptor-ligand engagement maintains hematopoietic stem cell quiescence and niche retention

Weihuan Wang, Shuiliang Yu, Grant Zimmerman, Yiwei Wang, Jay Myers, Vionnie W.C. Yu, Dan Huang, Xiaoran Huang, Jeongsup Shim, Yuanshuai Huang, William Xin, Peter Qiao, Minhong Yan, Wei Xin, David T. Scadden, Pamela Stanley, John B. Lowe, Alex Y. Huang, Christian W. Siebel, Lan Zhou

Research output: Contribution to journalArticle

19 Scopus citations

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. Stem Cells 2015;33:2280-2293

Original languageEnglish (US)
Pages (from-to)2280-2293
Number of pages14
JournalSTEM CELLS
Volume33
Issue number7
DOIs
StatePublished - Jul 1 2015

Keywords

  • HSC egress and mobilization
  • HSC quiescence and niche retention
  • Notch receptor-ligand interactions
  • O-fucosylglycans on Notch

ASJC Scopus subject areas

  • Molecular Medicine
  • Developmental Biology
  • Cell Biology

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  • Cite this

    Wang, W., Yu, S., Zimmerman, G., Wang, Y., Myers, J., Yu, V. W. C., Huang, D., Huang, X., Shim, J., Huang, Y., Xin, W., Qiao, P., Yan, M., Xin, W., Scadden, D. T., Stanley, P., Lowe, J. B., Huang, A. Y., Siebel, C. W., & Zhou, L. (2015). Notch receptor-ligand engagement maintains hematopoietic stem cell quiescence and niche retention. STEM CELLS, 33(7), 2280-2293. https://doi.org/10.1002/stem.2031