Vascular niche E-selectin regulates hematopoietic stem cell dormancy, self renewal and chemoresistance

Abstract

The microenvironment, or niche, surrounding a stem cell largely governs its cellular fate. Two anatomical niches for hematopoietic stem cells (HSCs) have been reported in the bone marrow, but a distinct function for each of these niches remains unclear. Here we report a new role for the adhesion molecule E-selectin expressed exclusively by bone marrow endothelial cells in the vascular HSC niche. HSC quiescence was enhanced and self-renewal potential was increased in E-selectin knockout (Sele−/−) mice or after administration of an E-selectin antagonist, demonstrating that E-selectin promotes HSC proliferation and is a crucial component of the vascular niche. These effects are not mediated by canonical E-selectin ligands. Deletion or blockade of E-selectin enhances HSC survival threefold to sixfold after treatment of mice with chemotherapeutic agents or irradiation and accelerates blood neutrophil recovery. As bone marrow suppression is a severe side effect of high-dose chemotherapy, transient blockade of E-selectin is potentially a promising treatment for the protection of HSCs during chemotherapy or irradiation.

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Figure 1: HSC quiescence is increased in E-selectin knockout (Sele−/−) mice.
Figure 2: The effect of E-selectin on HSC turnover is mediated by the bone marrow microenvironment.
Figure 3: E-selectin–expressing endothelial cells are enriched in the endosteal region.
Figure 4: HSCs from Sele−/− mice are chemoresistant and radioresistant.
Figure 5: Administration of a small, synthetic E-selectin antagonist enhances HSC quiescence, chemoresistance, self-renewal capacity and blood leukocyte recovery after chemotherapy.
Figure 6: PSGL-1 and CD44 receptors do not mediate the effects of E-selectin on HSC cycling.

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Acknowledgements

The authors wish to thank R. Wadley for assistance with cell sorting, P. Frenette (Albert Einstein College of Medicine, New York) for providing selectin knockout mice, B. Furie (Beth Israel Deaconess Medical Center, Harvard Medical School, Boston) for Selplg−/− mice, T. Mak (Ontario Cancer Institute, Toronto) for Cd44−/− mice, D. Vestweber (Max Planck Institute of Molecular Biomedicine, Münster, Germany) for antibody to ESL-1, K. Snapp (Northwestern University, Chicago) for selectin-IgM constructs and L. Purton, C. Walkley and C. Bonder for helpful discussions. This work was supported by project grants 350406 and 543706 (I.G.W. and J.-P.L.) and Career Development Fellowships 488817 and APP1033736 (I.G.W.) from the National Health and Medical Research Council of Australia, a Senior Research Fellowship from the Cancer Council of Queensland (J.-P.L.) and a research contract with GlycoMimetics Inc to generate the data in Figure 5.

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I.G.W. initiated, conceived of, designed and supervised research, wrote the manuscript, performed experiments and analyzed data. V.B., B.N., R.N.J. and C.E.F. performed experiments and analyzed data. J.T.P. and J.L.M. contributed vital new reagents and commented on the research direction. J.-P.L. initiated the study, supervised research direction and experiments, performed some experiments and edited the manuscript. All authors discussed and commented on the manuscript.

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Correspondence to Ingrid G Winkler or Jean-Pierre Lévesque.

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J.L.M. and J.T.P. are employees of GlycoMimetics Inc and own shares in the company. GlycoMimetics funded the work shown in Figure 5 involving GMI-1070.

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Winkler, I., Barbier, V., Nowlan, B. et al. Vascular niche E-selectin regulates hematopoietic stem cell dormancy, self renewal and chemoresistance. Nat Med 18, 1651–1657 (2012). https://doi.org/10.1038/nm.2969

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