J. Exp. Med., Volume 188, Number 2, July 20, 1998 393-398

The Fluctuating Phenotype of the Lymphohematopoietic Stem Cell with Cell Cycle Transit

By Houri K. Habibian,^* Stefan O. Peters,^* C.C. Hsieh, Joanne Wuu,^* Kristin Vergilis,^* Christina I. Grimaldi,^* Judith Reilly,^* Jane E. Carlson,^* Angela E. Frimberger,^* F.M. Stewart, and Peter J. Quesenberry^§

From the ^* Cancer Center, the  Department of Medicine, and the ^§ Department of Cell Biology, University of Massachusetts Medical Center, Worcester, Massachusetts 01605

The most primitive engrafting hematopoietic stem cell has been assumed to have a fixed phenotype, with changes in engraftment and renewal potential occurring in a stepwise irreversible fashion linked with differentiation. Recent work shows that in vitro cytokine stimulation of murine marrow cells induces cell cycle transit of primitive stem cells, taking 40 h for progression from G₀ to mitosis and 12 h for subsequent doublings. At 48 h of culture, progenitors are expanded, but stem cell engraftment is markedly diminished. We have investigated whether this effect on engraftment was an irreversible step or a reversible plastic feature correlated with cell cycle progression. Long-term engraftment (2 and 6 mo) of male BALB/c marrow cells exposed in vitro to interleukin (IL)-3, IL-6, IL-11, and steel factor was assessed at 2-4-h intervals of culture over 24-48 h using irradiated female hosts; the engraftment phenotype showed marked fluctuations over 2-4-h intervals, with engraftment nadirs occurring in late S and early G₂. These data show that early stem cell regulation is cell cycle based, and have critical implications for strategies for stem cell expansion and engraftment or gene therapy, since position in cell cycle will determine whether effective engraftment occurs in either setting.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

• Kent, D. G., Dykstra, B. J., Cheyne, J., Ma, E., Eaves, C. J. (2008). Steel factor coordinately regulates the molecular signature and biologic function of hematopoietic stem cells. Blood 112: 560-567 [Abstract] [Full Text]  
• Brenner, S., Ryser, M. F., Whiting-Theobald, N. L., Gentsch, M., Linton, G. F., Malech, H. L. (2007). The Late Dividing Population of {gamma}-Retroviral Vector Transduced Human Mobilized Peripheral Blood Progenitor Cells Contributes Most to Gene-Marked Cell Engraftment in Nonobese Diabetic/Severe Combined Immunodeficient Mice. Stem Cells 25: 1807-1813 [Abstract] [Full Text]  
• QUESENBERRY, P. J., COLVIN, G., DOONER, G., DOONER, M., ALIOTTA, J. M., JOHNSON, K. (2007). The Stem Cell Continuum: Cell Cycle, Injury, and Phenotype Lability. Ann. N. Y. Acad. Sci. 1106: 20-29 [Abstract] [Full Text]  
• Araki, H., Yoshinaga, K., Boccuni, P., Zhao, Y., Hoffman, R., Mahmud, N. (2007). Chromatin-modifying agents permit human hematopoietic stem cells to undergo multiple cell divisions while retaining their repopulating potential. Blood 109: 3570-3578 [Abstract] [Full Text]  
• Nygren, J. M., Bryder, D., Jacobsen, S. E. W. (2006). Prolonged Cell Cycle Transit Is a Defining and Developmentally Conserved Hemopoietic Stem Cell Property. J. Immunol. 177: 201-208 [Abstract] [Full Text]  
• Dykstra, B., Ramunas, J., Kent, D., McCaffrey, L., Szumsky, E., Kelly, L., Farn, K., Blaylock, A., Eaves, C., Jervis, E. (2006). High-resolution video monitoring of hematopoietic stem cells cultured in single-cell arrays identifies new features of self-renewal. Proc. Natl. Acad. Sci. USA 103: 8185-8190 [Abstract] [Full Text]  
• Liang, Y., Van Zant, G., Szilvassy, S. J. (2005). Effects of aging on the homing and engraftment of murine hematopoietic stem and progenitor cells. Blood 106: 1479-1487 [Abstract] [Full Text]  
• Leibundgut, K., Schmitz, N. M.R., Hirt, A. (2005). Catalytic Activities of G1 Cyclin-Dependent Kinases and Phosphorylation of Retinoblastoma Protein in Mobilized Peripheral Blood CD34+ Hematopoietic Progenitor Cells. Stem Cells 23: 1002-1011 [Abstract] [Full Text]  
• QUESENBERRY, P. J., COLVIN, G. A., ABEDI, M., DOONER, G., DOONER, M., ALIOTTA, J., KEANEY, P., LUO, L., DEMERS, D., PETERSON, A., FOSTER, B., GREER, D. (2005). The Stem Cell Continuum. Ann. N. Y. Acad. Sci. 1044: 228-235 [Abstract] [Full Text]  
• De Felice, L., Tatarelli, C., Mascolo, M. G., Gregorj, C., Agostini, F., Fiorini, R., Gelmetti, V., Pascale, S., Padula, F., Petrucci, M. T., Arcese, W., Nervi, C. (2005). Histone Deacetylase Inhibitor Valproic Acid Enhances the Cytokine-Induced Expansion of Human Hematopoietic Stem Cells. Cancer Res. 65: 1505-1513 [Abstract] [Full Text]  
• Roeder, I., Kamminga, L. M., Braesel, K., Dontje, B., de Haan, G., Loeffler, M. (2005). Competitive clonal hematopoiesis in mouse chimeras explained by a stochastic model of stem cell organization. Blood 105: 609-616 [Abstract] [Full Text]  
• Ahmed, F., Ings, S. J., Pizzey, A. R., Blundell, M. P., Thrasher, A. J., Ye, H. T., Fahey, A., Linch, D. C., Yong, K. L. (2004). Impaired bone marrow homing of cytokine-activated CD34+ cells in the NOD/SCID model. Blood 103: 2079-2087 [Abstract] [Full Text]  
• Munoz-Elias, G., Woodbury, D., Black, I. B. (2003). Marrow Stromal Cells, Mitosis, and Neuronal Differentiation: Stem Cell and Precursor Functions. Stem Cells 21: 437-448 [Abstract] [Full Text]  
• Lambert, J.-F., Liu, M., Colvin, G. A., Dooner, M., McAuliffe, C. I., Becker, P. S., Forget, B. G., Weissman, S. M., Quesenberry, P. J. (2003). Marrow Stem Cells Shift Gene Expression and Engraftment Phenotype with Cell Cycle Transit. J. Exp. Med. 197: 1563-1572 [Abstract] [Full Text]  
• QUESENBERRY, P., COLVIN, G., LAMBERT, J. F., ABEDI, M., CERNY, J., DOONER, M., MOORE, B., McAULIFFE, C., DEMERS, D., GREER, D., PARENT, A., BADIAVAS, E., LUM, L., FALANGA, V. (2003). Marrow Stem Cell Potential within a Continuum. Ann. N. Y. Acad. Sci. 996: 209-221 [Abstract] [Full Text]  
• Hematti, P., Sellers, S. E., Agricola, B. A., Metzger, M. E., Donahue, R. E., Dunbar, C. E. (2003). Retroviral transduction efficiency of G-CSF+SCF-mobilized peripheral blood CD34+ cells is superior to G-CSF or G-CSF+Flt3-L-mobilized cells in nonhuman primates. Blood 101: 2199-2205 [Abstract] [Full Text]  
• Quesenberry, P. J., Colvin, G. A., Lambert, J.-F. (2002). The chiaroscuro stem cell: a unified stem cell theory. Blood 100: 4266-4271 [Abstract] [Full Text]  
• Cashman, J., Dykstra, B., Clark-Lewis, I., Eaves, A., Eaves, C. (2002). Changes in the Proliferative Activity of Human Hematopoietic Stem Cells in NOD/SCID Mice and Enhancement of Their Transplantability after In Vivo Treatment with Cell Cycle Inhibitors. J. Exp. Med. 196: 1141-1150 [Abstract] [Full Text]  
• Huygen, S., Giet, O., Artisien, V., Di Stefano, I., Beguin, Y., Gothot, A. (2002). Adhesion of synchronized human hematopoietic progenitor cells to fibronectin and vascular cell adhesion molecule-1 fluctuates reversibly during cell cycle transit in ex vivo culture. Blood 100: 2744-2752 [Abstract] [Full Text]  
• Wilpshaar, J., Bhatia, M., Kanhai, H. H. H., Breese, R., Heilman, D. K., Johnson, C. S., Falkenburg, J. H. F., Srour, E. F. (2002). Engraftment potential of human fetal hematopoietic cells in NOD/SCID mice is not restricted to mitotically quiescent cells. Blood 100: 120-127 [Abstract] [Full Text]  
• Noach, E. J. K., Ausema, A., Dillingh, J. H., Dontje, B., Weersing, E., Akkerman, I., Vellenga, E., de Haan, G. (2002). Growth factor treatment prior to low-dose total body irradiation increases donor cell engraftment after bone marrow transplantation in mice. Blood 100: 312-317 [Abstract] [Full Text]  
• Hossle, J. P., Seger, R. A., Steinhoff, D. (2002). Gene Therapy of Hematopoietic Stem Cells: Strategies for Improvement. Physiology 17: 87-92 [Abstract] [Full Text]  
• Glimm, H., Tang, P., Clark-Lewis, I., von Kalle, C., Eaves, C. (2002). Ex vivo treatment of proliferating human cord blood stem cells with stroma-derived factor-1 enhances their ability to engraft NOD/SCID mice. Blood 99: 3454-3457 [Abstract] [Full Text]  
• Giet, O., Van Bockstaele, D. R., Di Stefano, I., Huygen, S., Greimers, R., Beguin, Y., Gothot, A. (2002). Increased binding and defective migration across fibronectin of cycling hematopoietic progenitor cells. Blood 99: 2023-2031 [Abstract] [Full Text]  
• Dao, M. A., Hwa, J., Nolta, J. A. (2002). Molecular mechanism of transforming growth factor beta -mediated cell-cycle modulation in primary human CD34+ progenitors. Blood 99: 499-506 [Abstract] [Full Text]  
• Szilvassy, S. J., Meyerrose, T. E., Ragland, P. L., Grimes, B. (2001). Differential homing and engraftment properties of hematopoietic progenitor cells from murine bone marrow, mobilized peripheral blood, and fetal liver. Blood 98: 2108-2115 [Abstract] [Full Text]  
• Drouet, M., Herodin, F., Norol, F., Mourcin, F., Mayol, J.F. (2001). Cell Cycle Activation of Peripheral Blood Stem and Progenitor Cells Expanded Ex Vivo with SCF, FLT-3 Ligand, TPO, and IL-3 Results in Accelerated Granulocyte Recovery in a Baboon Model of Autologous Transplantation but G0/G1 and S/G2/M Graft Cell Content Does Not Correlate with Tranplantability. Stem Cells 19: 436-442 [Abstract] [Full Text]  
• Frimberger, A. E., Stering, A. I., Quesenberry, P. J. (2001). An in vitro model of hematopoietic stem cell homing demonstrates rapid homing and maintenance of engraftable stem cells. Blood 98: 1012-1018 [Abstract] [Full Text]  
• QUESENBERRY, P. J., STEWART, F. M., BECKER, P., D'HONDT, L., FRIMBERGER, A., LAMBERT, J. F., COLVIN, G. A., MILLER, C., HEYES, C., ABEDI, M., DOONER, M., CARLSON, J., REILLY, J., McAULIFFE, C., STENCEL, K., BALLEN, K., EMMONS, R., DOYLE, P., ZHONG, S., WANG, H., HABIBIAN, H. (2001). Stem Cell Engraftment Strategies. Ann. N. Y. Acad. Sci. 938: 54-62 [Abstract] [Full Text]  
• Eaves, C., Glimm, H., Eisterer, W., Audet, J., Maguer-Satta, V., Pireta, J. (2001). Characterization of Human Hematopoietic Cells with Short-Lived in Vivo Repopulating Activity. Ann. N. Y. Acad. Sci. 938: 63-71 [Abstract] [Full Text]  
• DUNBAR, C. E., TAKATOKU, M., DONAHUE, R. E. (2001). The Impact of ex Vivo Cytokine Stimulation on Engraftment of Primitive Hematopoietic Cells in a Non-Human Primate Model. Ann. N. Y. Acad. Sci. 938: 236-245 [Abstract] [Full Text]  
• Glimm, H., Oh, I.-H., Eaves, C. J. (2000). Human hematopoietic stem cells stimulated to proliferate in vitro lose engraftment potential during their S/G2/M transit and do not reenter G0. Blood 96: 4185-4193 [Abstract] [Full Text]  
• Cashman, J. D., Eaves, C. J. (2000). High marrow seeding efficiency of human lymphomyeloid repopulating cells in irradiated NOD/SCID mice. Blood 96: 3979-3981 [Abstract] [Full Text]  
• Rosler, E. S., Brandt, J. E., Chute, J., Hoffman, R. (2000). An in vivo competitive repopulation assay for various sources of human hematopoietic stem cells. Blood 96: 3414-3421 [Abstract] [Full Text]  
• Bryder, D., Jacobsen, S. E. W. (2000). Interleukin-3 supports expansion of long-term multilineage repopulating activity after multiple stem cell divisions in vitro. Blood 96: 1748-1755 [Abstract] [Full Text]  
• Zandstra, P. W., Lauffenburger, D. A., Eaves, C. J. (2000). A ligand-receptor signaling threshold model of stem cell differentiation control: a biologically conserved mechanism applicable to hematopoiesis. Blood 96: 1215-1222 [Abstract] [Full Text]  
• Klug, C. A., Cheshier, S., Weissman, I. L. (2000). Inactivation of a GFP retrovirus occurs at multiple levels in long-term repopulating stem cells and their differentiated progeny. Blood 96: 894-901 [Abstract] [Full Text]  
• Szilvassy, S. J., Meyerrose, T. E., Grimes, B. (2000). Effects of cell cycle activation on the short-term engraftment properties of ex vivo expanded murine hematopoietic cells. Blood 95: 2829-2837 [Abstract] [Full Text]  
• Oostendorp, R. A. J., Audet, J., Eaves, C. J. (2000). High-resolution tracking of cell division suggests similar cell cycle kinetics of hematopoietic stem cells stimulated in vitro and in vivo. Blood 95: 855-862 [Abstract] [Full Text]  
• Glimm, H., Eaves, C.J. (1999). Direct Evidence for Multiple Self-Renewal Divisions of Human In Vivo Repopulating Hematopoietic Cells in Short-Term Culture. Blood 94: 2161-2168 [Abstract] [Full Text]  
• Holyoake, T., Jiang, X., Eaves, C., Eaves, A. (1999). Isolation of a Highly Quiescent Subpopulation of Primitive Leukemic Cells in Chronic Myeloid Leukemia. Blood 94: 2056-2064 [Abstract] [Full Text]  
• QUESENBERRY, P. J., STEWART, F. M., ZHONG, S., HABIBIAN, H., MCAULIFFE, C., REILLY, J., CARLSON, J., DOONER, M., NILSSON, S., PETERS, S., STEIN, G., STEIN, J., EMMONS, R., BENOIT, B., BERTONCELLO, I., BECKER, P. (1999). Lymphohematopoietic Stem Cell Engraftment. Ann. N. Y. Acad. Sci. 872: 40-47 [Abstract] [Full Text]  
• Quesenberry, P. J., Becker, P. S. (1998). Stem cell homing: Rolling, crawling, and nesting. Proc. Natl. Acad. Sci. USA 95: 15155-15157 [Full Text]  

Home | Help | Feedback | Subscriptions | Archive | Search

TABLE OF CONTENTS