Control of human hematopoietic stem/progenitor cell migration by the extracellular matrix protein Slit3
Open accessAbstract
Patients whose hematopoietic system is compromised by chemo- and/or radiotherapy require transplantation of hematopoietic stem and progenitor cells (HSPCs) to restore hematopoiesis. Successful homing of transplanted HSPCs to the bone marrow (BM) largely depends on their migratory potential, which is critically regulated by the chemokine CXCL12. In this study, we have investigated the expression and function of Slit proteins and their corresponding Roundabout (Robo) receptors in human HSPC migration. Slit proteins are extracellular matrix proteins that can modulate the (chemoattractant-induced) migration of mature leukocytes. We show that mRNAs for all Slits (Slit1-3) are expressed in primary BM stroma and BM-derived endothelial and stromal cell lines, but not in CD34⁺ HSPCs. Human CD34⁺ HSPCs expressed mRNAs for all Robos (Robo1-4), but only the Robo1 protein was detected on their cell surface. Functionally, Slit3 treatment increased the in vivo homing efficiency of CD34⁺ HSPCs to the BM in NOD/SCID mice, whereas Slit3-exposed HSPC migration in vitro was inhibited. These effects do not appear to result from modulated CXCL12 responsiveness as CXCR4 expression, CXCL12-induced actin polymerization or the basal and CXCL12-induced adhesion to fibronectin or BM-derived endothelial cells of CD34⁺ HSPC were not altered by Slit3 exposure. However, we show that Slit3 rapidly reduced the levels of active RhoA in HL60 cells and primary CD34⁺ HSPC, directly affecting a pathway involved in actin cytoskeleton remodeling and HSPC migration. Together, our results support a role for Slit3 in human HSPC migration in vitro and homing in vivo and might contribute to the design of future approaches aimed at improving transplantation efficiency of human CD34⁺ HSPCs.
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Formation of H vessels is supported by production of SLIT3 in osteoclasts, which also enhances H vessel branching.
“The formation of H vessels is supported by the production of the slit homolog 3 (SLIT3) protein in osteoclasts,131 which also enhances H vessel branching.131–133”
From Bone remodeling: an operational process ensuring survival and bone mechanical competence (2022) · cites this paper as [133]
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Cites
Traffic signals for lymphocyte recirculation and leukocyte emigration: The multistep paradigm
Springer, T. A. (1994) · Cell · doi:10.1016/0092-8674(94)90337-9 · Cited by 7,009 · see citing works
Osteoblastic cells regulate the haematopoietic stem cell niche
Calvi, L. M., Adams, G. B., Weibrecht, K. W., Weber, J. M., Olson, D. P., Knight, M. C., Martin, R. P., Schipani, E., Pajevic, P. D., Bringhurst, F. R., et al. (2003) · Nature · doi:10.1038/nature02040 · Cited by 3,433 · see citing works
Identification of the haematopoietic stem cell niche and control of the niche size
Zhang, J., Niu, C. S., Ye, L., Huang, H., He, X. C., Tong, W.-G., Ross, J., Haug, J., Johnson, T. J., Feng, J. Q., et al. (2003) · Nature · doi:10.1038/nature02041 · Cited by 2,948 · see citing works
Dependence of Human Stem Cell Engraftment and Repopulation of NOD/SCID Mice on CXCR4
Peled, A., Petit, I., Kollet, O., Magid, M., Ponomaryov, T., Byk, T., Nagler, A., Ben-Hur, H., Many, A., Shultz, L., et al. (1999) · Science · doi:10.1126/science.283.5403.845 · Cited by 1,644 · see citing works
Aiuti, A., Webb, I. J., Bleul, C. C., Springer, T. A., & Gutierrez‐Ramos, J. C. (1997) · The Journal of Experimental Medicine · doi:10.1084/jem.185.1.111 · Cited by 1,378 · see citing works
Brose, K., Bland, K. S., Wang, K. H., Arnott, D., Henzel, W., Goodman, C., Tessier-Lavigne, M., & Kidd, T. (1999) · Cell · doi:10.1016/s0092-8674(00)80590-5 · Cited by 1,276 · see citing works
Slit Is the Midline Repellent for the Robo Receptor in Drosophila
Kidd, T., Bland, K. S., & Goodman, C. S. (1999) · Cell · doi:10.1016/s0092-8674(00)80589-9 · Cited by 953 · see citing works
Kidd, T., Brose, K., Mitchell, K. J., Fetter, R. D., Tessier‐Lavigne, M., Goodman, C. S., & Tear, G. (1998) · Cell · doi:10.1016/s0092-8674(00)80915-0 · Cited by 882 · see citing works
Beillard, E. J., Pallisgaard, N., van der Velden, V. H. J., Bi, W., Dee, R., van der Schoot, C. E., Delabesse, É., Macintyre, E. A., Gottardi, E. M., Saglio, G. N., et al. (2003) · Leukemia · doi:10.1038/sj.leu.2403136 · Cited by 880 · see citing works
Omatsu, Y., Sugiyama, T., Kohara, H., Kondoh, G., Fujii, N., Kohno, K., & Nagasawa, T. (2010) · Immunity · doi:10.1016/j.immuni.2010.08.017 · Cited by 849 · see citing works
Peled, A., Kollet, Ó., Ponomaryov, T., Petit, I., Franitza, S., Grabovsky, V., Magid, M., Nagler, A., Lider, O., Alon, R., et al. (2000) · Blood · doi:10.1182/blood.v95.11.3289 · Cited by 764 · see citing works
RhoA is required for monocyte tail retraction during transendothelial migration
Worthylake, R. A., Lemoine, S., Watson, J. M., & Burridge, K. (2001) · The Journal of Cell Biology · doi:10.1083/jcb.200103048 · Cited by 501 · see citing works
The neuronal repellent Slit inhibits leukocyte chemotaxis induced by chemotactic factors
Wu, J. Y., Feng, L., Park, H.-T., Havlioglu, N., Wen, L., Tang, H., Bacon, K. B., Jiang, Z., Zhang, X.-C., & Rao, Y. (2001) · Nature · doi:10.1038/35073616 · Cited by 397 · see citing works
Dar, A., Goichberg, P., Shinder, V., Kalinkovich, A., Kollet, Ó., Netzer, N., Margalit, R., Zsak, M., Nagler, A., Hardan, I., et al. (2005) · Nature Immunology · doi:10.1038/ni1251 · Cited by 364 · see citing works
Huminiecki, Ł., Gorn, M., Suchting, S., Poulsom, R., & Bicknell, R. (2002) · Genomics · doi:10.1006/geno.2002.6745 · Cited by 330 · see citing works
Short-Range and Long-Range Guidance by Slit and Its Robo Receptors
Simpson, J. H., Bland, K. S., Fetter, R. D., & Goodman, C. S. (2000) · Cell · doi:10.1016/s0092-8674(00)00206-3 · Cited by 304 · see citing works
Active movement of T cells away from a chemokine
Poznansky, M. C., Olszak, I. T., Foxall, R. B., Evans, R. H., Luster, A. D., & Scadden, D. T. (2000) · Nature Medicine · doi:10.1038/75022 · Cited by 301 · see citing works
Yuan, W., Zhou, L., Chen, J., Wu, J. Y., Rao, Y., & Ornitz, D. M. (1999) · Developmental Biology · doi:10.1006/dbio.1999.9371 · Cited by 299 · see citing works
Kollet, Ó., Spiegel, A., Peled, A., Petit, I., Byk, T., Hershkoviz, R., Guetta, E., Barkai, G., Nagler, A., & Lapidot, T. (2001) · Blood · doi:10.1182/blood.v97.10.3283 · Cited by 290 · see citing works
Kramer, S. G., Kidd, T., Simpson, J. H., & Goodman, C. S. (2001) · Science · doi:10.1126/science.1058766 · Cited by 238 · see citing works
Short-Range and Long-Range Guidance by Slit and Its Robo Receptors
Simpson, J. H., Kidd, T., Bland, K. S., & Goodman, C. S. (2000) · Neuron · doi:10.1016/s0896-6273(00)00151-3 · Cited by 229 · see citing works
Cell-surface heparan sulfate is involved in the repulsive guidance activities of Slit2 protein
Hu, H. (2001) · Nature Neuroscience · doi:10.1038/89482 · Cited by 201 · see citing works
Repulsive axon guidance molecule Slit3 is a novel angiogenic factor
Zhang, B., Dietrich, U. M., Geng, J.-G., Bicknell, R., Esko, J. D., & Wang, L. (2009) · Blood · doi:10.1182/blood-2008-12-193326 · Cited by 163 · see citing works
Andrews, W. D., Barber, M., Hernandez-Miranda, L. R., Xian, J., Rakić, S., Sundaresan, V., Rabbitts, T. H., Pannell, R., Rabbitts, P. H., Thompson, H., et al. (2007) · Developmental Biology · doi:10.1016/j.ydbio.2007.10.052 · Cited by 152 · see citing works
Self-citationCXCR-4 Desensitization Is Associated with Tissue Localization of Hemopoietic Progenitor Cells
Shen, H., Cheng, T., Olszak, I. T., et al. (2001) · The Journal of Immunology · doi:10.4049/jimmunol.166.8.5027 · Cited by 150 · see citing works
Robo4 Cooperates with Cxcr4 to Specify Hematopoietic Stem Cell Localization to Bone Marrow Niches
Smith‐Berdan, S., Nguyen, A., Hassanein, D., Zimmer, M., Ugarte, F., Ciriza, J., Li, D., García‐Ojeda, M. E., Hinck, L., & Forsberg, E. C. (2011) · Cell stem cell · doi:10.1016/j.stem.2010.11.030 · Cited by 133 · see citing works
CXCL12 and C5a trigger cell migration via a PAK1/2-p38α MAPK-MAPKAP-K2-HSP27 pathway
Rousseau, S., Dolado, I., Beardmore, V. A., Shpiro, N., Márquez, R., Nebreda, Á. R., Arthur, J. S. C., Case, L. C., Tessier‐Lavigne, M., Gaestel, M., et al. (2006) · Cellular Signalling · doi:10.1016/j.cellsig.2006.02.006 · Cited by 126 · see citing works
Cloning and Functional Studies of a Novel Gene Aberrantly Expressed in RB-Deficient Embryos
Yuan, S. F., Cox, L. A., Dasika, G. K., & Lee, E. Y.-H. P. (1999) · Developmental Biology · doi:10.1006/dbio.1998.9141 · Cited by 119 · see citing works
Slit-2/Robo-1 modulates the CXCL12/CXCR4-induced chemotaxis of T cells
Prasad, A., Qamri, Z., Wu, J. Y., et al. (2007) · Journal of Leukocyte Biology · doi:10.1189/jlb.1106678 · Cited by 119 · see citing works
van Hennik, P. B., de Koning, A. E., & Ploemacher, R. E. (1999) · Blood · doi:10.1182/blood.v94.9.3055 · Cited by 118 · see citing works
Extracellular Ig domains 1 and 2 of Robo are important for ligand (Slit) binding
Liu, Z., Patel, K., Schmidt, H., et al. (2004) · Molecular and Cellular Neuroscience · doi:10.1016/j.mcn.2004.01.002 · Cited by 115 · see citing works
Chen, J., Wen, L., Dupuis, S., Wu, J. Y., & Rao, Y. (2001) · Journal of Neuroscience · doi:10.1523/jneurosci.21-05-01548.2001 · Cited by 113 · see citing works
Fukuda, S., Bian, H., King, A. G., et al. (2007) · Blood · doi:10.1182/blood-2006-06-031401 · Cited by 110 · see citing works
Peng, S.-B., Peek, V. L., Zhai, Y., Paul, D. C., Lou, Q., Xia, X., Eessalu, T. E., Kohn, W. D., & Tang, S. (2005) · Molecular Cancer Research · doi:10.1158/1541-7786.mcr-04-0193 · Cited by 107 · see citing works
Sensory Axon Response to Substrate-Bound Slit2 Is Modulated by Laminin and Cyclic GMP
Nguyen-Ba-Charvet, K. T., Brose, K., Marillat, V., Sotelo, C., Tessier‐Lavigne, M., & Chédotal, A. (2001) · Molecular and Cellular Neuroscience · doi:10.1006/mcne.2001.0994 · Cited by 96 · see citing works
Thalmeier, K., Meissner, W. G., Reisbach, G., et al. (1994) · Blood · doi:10.1182/blood.v83.7.1799.1799 · Cited by 93 · see citing works
Ghiaur, G., Lee, A. W.-T., Bailey, J., Cancelas, J. A., Zheng, Y., & Williams, D. A. (2006) · Blood · doi:10.1182/blood-2006-02-001560 · Cited by 89 · see citing works
Hierarchy of molecular-pathway usage in bone marrow homing and its shift by cytokines
Bonig, H. B., Priestley, G. V., & Papayannopoulou, T. (2005) · Blood · doi:10.1182/blood-2005-05-2023 · Cited by 87 · see citing works
Cancelas, J. A., Jansen, M., & Williams, D. A. (2006) · Experimental Hematology · doi:10.1016/j.exphem.2006.03.016 · Cited by 87 · see citing works
Stromal Cell-Derived Factor-1 Antagonizes Slit/Robo SignalingIn Vivo
Chalasani, S. H., Sabol, A., Xu, H. A., Gyda, M., Rasband, K., Granato, M., Chien, C.-B., & Raper, J. A. (2007) · Journal of Neuroscience · doi:10.1523/jneurosci.4132-06.2007 · Cited by 87 · see citing works
Immortalisation of human bone marrow endothelial cells: characterisation of new cell lines
Rood, Calafat, Borne, K. V. D., Gerritsen, & Schoot, V. D. (2000) · European Journal of Clinical Investigation · doi:10.1046/j.1365-2362.2000.00672.x · Cited by 71 · see citing works
CD64/Fc gamma RI is a granulo-monocytic lineage marker on CD34+ hematopoietic progenitor cells
Olweus, J., Lund‐Johansen, F., & Terstappen, L. W. M. M. (1995) · Blood · doi:10.1182/blood.v85.9.2402.bloodjournal8592402 · Cited by 67 · see citing works
Chen, B., Blair, D. G., Plisov, S. Y., et al. (2004) · The Journal of Immunology · doi:10.4049/jimmunol.173.10.5914 · Cited by 63 · see citing works
Fonseca, A., Freund, D., Bornhäuser, M., & Corbeil, D. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.145037 · Cited by 60 · see citing works
The Chemorepellent Slit3 Promotes Monocyte Migration
Geutskens, S. B., Hordijk, P. L., & van Hennik, P. B. (2010) · The Journal of Immunology · doi:10.4049/jimmunol.0903898 · Cited by 56 · see citing works
Self-citationSlit proteins are not dominant chemorepellents for olfactory tract and spinal motor axons
Patel, K., Nash, J. A. B., Itoh, A., et al. (2001) · Development · doi:10.1242/dev.128.24.5031 · Cited by 47 · see citing works
Shibata, F., Goto‐Koshino, Y., Morikawa, Y., Komori, T., Ito, M., Fukuchi, Y., Houchins, J. P., Tsang, M., Li, D. Y., Kitamura, T., et al. (2008) · Stem Cells · doi:10.1634/stemcells.2008-0292 · Cited by 42 · see citing works
Arai, A., Jin, A., Weihua, Y., Mizuchi, D., Yamamoto, K., Nanki, T., & Miura, O. (2004) · Cellular Signalling · doi:10.1016/j.cellsig.2004.09.007 · Cited by 35 · see citing works
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Research works printed but not linked: 1
- Chalasani SH, Sabol A, Xu H, et al. Stromal cell-derivedfactor-1 antagonizes slit/robo signaling in vivo. J Neurosci 2007;27:973-980.
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Bone remodeling: an operational process ensuring survival and bone mechanical competence
Bolamperti, S., Villa, I., & Rubinacci, A. (2022) · Bone Research · doi:10.1038/s41413-022-00219-8 · Cited by 482 · see citing works
- Authors
- Geutskens, S. B., Andrews, W. D., van Stalborch, A.-M. D., Brussen, K., Holtrop-de Haan, S. E., Parnavelas, J. G., Hordijk, P. L., & van Hennik, P. B.
- Affiliations
- Amsterdam UMC Location University of Amsterdam (NL)
- University College London (GB)
- Corresponding author
- Geutskens, Sacha B
- Venue
- Laboratory Investigation
- Publisher
- Elsevier BV
- Published
- 2012-08
- Volume
- 92
- Issue
- 8
- Pages
- 1129-1139
- ISSN
- 0023-6837 (ISSN-L)
- OpenAlex
- W2042449456
- Cited by
- 34
- References
- 48
- Citations by year
- 2026: 1 · 2024: 1 · 2023: 2 · 2022: 5 · 2021: 4 · 2020: 1 · 2019: 3 · 2018: 3 · 2017: 3 · 2016: 2 · 2015: 3 · 2014: 3 · 2013: 2 · 2012: 1
- FWCI
- 1.92
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Laboratory Investigation (publishedVersion)
- PubMed (publishedVersion)
- Amsterdam UMC (VU Amsterdam) - Institutional Repository (publishedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Pure Amsterdam UMC (submittedVersion)
- Funders
- Nederlandse Organisatie voor Wetenschappelijk Onderzoek
- Topics
- Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Axon Guidance and Neuronal Signaling
- Health Sciences › Medicine › Oncology › Chemokine receptors and signaling
- Keywords
- SLIT3, hematopoietic stem and progenitor cells, cell migration, homing, bone marrow, Roundabout receptors, ROBO1, RhoA, actin cytoskeleton, CXCL12, CXCR4, extracellular matrix, hematopoietic stem cell transplantation, CD34+ cells, bone marrow stroma
- MeSH terms
- Roundabout Proteins, Animals, Bone Marrow Cells, Cell Adhesion, Cell Movement, Cells, Cultured, Flow Cytometry, Hematopoietic Stem Cells, Humans, Membrane Proteins, Nerve Tissue Proteins, Receptors, Immunologic, Spleen, Antigens, CD, Mice, SCID, Receptors, CXCR4, rhoA GTP-Binding Protein, Stem Cell Transplantation, Cell Line, Tumor, Mice, Chemokine CXCL12
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