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

doi:10.1002/stem.2031

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 journal › Article › peer-review

33 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-J_K-mediated canonical Notch signaling. Furthermore, Notch-ligand neutralizing antibodies induce RBP-J_K-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.

Original language	English (US)
Pages (from-to)	2280-2293
Number of pages	14
Journal	STEM CELLS
Volume	33
Issue number	7
DOIs	https://doi.org/10.1002/stem.2031
State	Published - 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

Medicine(all)

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10.1002/stem.2031

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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

Wang, W, Yu, S, Zimmerman, G, Wang, Y, Myers, J, Yu, VWC, Huang, D, Huang, X, Shim, J, Huang, Y, Xin, W, Qiao, P, Yan, M, Xin, W, Scadden, DT, Stanley, P, Lowe, JB, Huang, AY, Siebel, CW & Zhou, L 2015, 'Notch receptor-ligand engagement maintains hematopoietic stem cell quiescence and niche retention', STEM CELLS, vol. 33, no. 7, pp. 2280-2293. https://doi.org/10.1002/stem.2031

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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.",

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AU - Wang, Weihuan

AU - Yu, Shuiliang

AU - Zimmerman, Grant

AU - Wang, Yiwei

AU - Myers, Jay

AU - Yu, Vionnie W.C.

AU - Huang, Dan

AU - Huang, Xiaoran

AU - Shim, Jeongsup

AU - Huang, Yuanshuai

AU - Xin, William

AU - Qiao, Peter

AU - Yan, Minhong

AU - Xin, Wei

AU - Scadden, David T.

AU - Stanley, Pamela

AU - Lowe, John B.

AU - Huang, Alex Y.

AU - Siebel, Christian W.

AU - Zhou, Lan

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N2 - 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.

AB - 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.

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

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