J. Exp. Med., Volume 189, Number 7, April 5, 1999 1139-1148

Bone Morphogenetic Proteins Regulate the Developmental Program of Human Hematopoietic Stem Cells

By Mickie Bhatia,^* Dominique Bonnet, Dongmei Wu,^* Barbara Murdoch, Jeff Wrana, Lisa Gallacher,^* and John E. Dick

From the ^* Department of Gene Therapy and Molecular Virology, The John P. Robarts Research Institute, and the Department of Microbiology and Immunology, University of  Western Ontario, London, Ontario N6A 5K8, Canada; and the  Program in Cancer/Blood and the Program in Developmental Biology, Research Institute, Hospital for Sick Children, and the Department of Molecular and Medical Genetics, University of Toronto, Toronto, Ontario M5G 1X8, Canada

The identification of molecules that regulate human hematopoietic stem cells has focused mainly on cytokines, of which very few are known to act directly on stem cells. Recent studies in lower organisms and the mouse have suggested that bone morphogenetic proteins (BMPs) may play a critical role in the specification of hematopoietic tissue from the mesodermal germ layer. Here we report that BMPs regulate the proliferation and differentiation of highly purified primitive human hematopoietic cells from adult and neonatal sources. Populations of rare CD34⁺CD38Lin stem cells were isolated from human hematopoietic tissue and were found to express the BMP type I receptors activin-like kinase (ALK)-3 and ALK-6, and their downstream transducers SMAD-1, -4, and -5. Treatment of isolated stem cell populations with soluble BMP-2, -4, and -7 induced dose-dependent changes in proliferation, clonogenicity, cell surface phenotype, and multilineage repopulation capacity after transplantation in nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice. Similar to transforming growth factor , treatment of purified cells with BMP-2 or -7 at high concentrations inhibited proliferation yet maintained the primitive CD34⁺CD38 phenotype and repopulation capacity. In contrast, low concentrations of BMP-4 induced proliferation and differentiation of CD34⁺ CD38Lin cells, whereas at higher concentrations BMP-4 extended the length of time that repopulation capacity could be maintained in ex vivo culture, indicating a direct effect on stem cell survival. The discovery that BMPs are capable of regulating repopulating cells provides a new pathway for controlling human stem cell development and a powerful model system for studying the biological mechanism of BMP action using primary human cells.

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

This article has been cited by other articles:

• Matsubara, E., Sakai, I., Yamanouchi, J., Fujiwara, H., Yakushijin, Y., Hato, T., Shigemoto, K., Yasukawa, M. (2009). The Role of Zinc Finger Protein 521/Early Hematopoietic Zinc Finger Protein in Erythroid Cell Differentiation. J. Biol. Chem. 284: 3480-3487 [Abstract] [Full Text]  
• Esterberg, R., Delalande, J.-M., Fritz, A. (2008). Tailbud-derived Bmp4 drives proliferation and inhibits maturation of zebrafish chordamesoderm. Development 135: 3891-3901 [Abstract] [Full Text]  
• Jeanpierre, S., Nicolini, F. E., Kaniewski, B., Dumontet, C., Rimokh, R., Puisieux, A., Maguer-Satta, V. (2008). BMP4 regulation of human megakaryocytic differentiation is involved in thrombopoietin signaling. Blood 112: 3154-3163 [Abstract] [Full Text]  
• Unger, C., Karner, E., Treschow, A., Stellan, B., Felldin, U., Concha, H., Wendel, M., Hovatta, O., Aints, A., Ahrlund-Richter, L., Dilber, M. S. (2008). Lentiviral-Mediated HoxB4 Expression in Human Embryonic Stem Cells Initiates Early Hematopoiesis in a Dose-Dependent Manner but Does Not Promote Myeloid Differentiation. Stem Cells 26: 2455-2466 [Abstract] [Full Text]  
• Jung, Y., Song, J., Shiozawa, Y., Wang, J., Wang, Z., Williams, B., Havens, A., Schneider, A., Ge, C., Franceschi, R. T., McCauley, L. K., Krebsbach, P. H., Taichman, R. S. (2008). Hematopoietic Stem Cells Regulate Mesenchymal Stromal Cell Induction into Osteoblasts Thereby Participating in the Formation of the Stem Cell Niche. Stem Cells 26: 2042-2051 [Abstract] [Full Text]  
• Wang, Q., Huang, Z., Xue, H., Jin, C., Ju, X.-L., Han, J.-D. J., Chen, Y.-G. (2008). MicroRNA miR-24 inhibits erythropoiesis by targeting activin type I receptor ALK4. Blood 111: 588-595 [Abstract] [Full Text]  
• Blank, U., Karlsson, G., Karlsson, S. (2008). Signaling pathways governing stem-cell fate. Blood 111: 492-503 [Abstract] [Full Text]  
• Durand, C., Robin, C., Bollerot, K., Baron, M. H., Ottersbach, K., Dzierzak, E. (2007). Embryonic stromal clones reveal developmental regulators of definitive hematopoietic stem cells. Proc. Natl. Acad. Sci. USA 104: 20838-20843 [Abstract] [Full Text]  
• Zhang, X.-B., Schwartz, J. L., Humphries, R. K., Kiem, H.-P. (2007). Effects of HOXB4 Overexpression on Ex Vivo Expansion and Immortalization of Hematopoietic Cells from Different Species. Stem Cells 25: 2074-2081 [Abstract] [Full Text]  
• Magnusson, M., Brun, A. C. M., Miyake, N., Larsson, J., Ehinger, M., Bjornsson, J. M., Wutz, A., Sigvardsson, M., Karlsson, S. (2007). HOXA10 is a critical regulator for hematopoietic stem cells and erythroid/megakaryocyte development. Blood 109: 3687-3696 [Abstract] [Full Text]  
• Tzachanis, D., Li, L., Lafuente, E. M., Berezovskaya, A., Freeman, G. J., Boussiotis, V. A. (2007). Twisted gastrulation (Tsg) is regulated by Tob and enhances TGF-{beta} signaling in activated T lymphocytes. Blood 109: 2944-2952 [Abstract] [Full Text]  
• Kaplan, F. S., Glaser, D. L., Shore, E. M., Pignolo, R. J., Xu, M., Zhang, Y., Senitzer, D., Forman, S. J., Emerson, S. G. (2007). Hematopoietic Stem-Cell Contribution to Ectopic Skeletogenesis. JBJS 89: 347-357 [Abstract] [Full Text]  
• Pimanda, J. E., Donaldson, I. J., de Bruijn, M. F. T. R., Kinston, S., Knezevic, K., Huckle, L., Piltz, S., Landry, J.-R., Green, A. R., Tannahill, D., Gottgens, B. (2007). The SCL transcriptional network and BMP signaling pathway interact to regulate RUNX1 activity. Proc. Natl. Acad. Sci. USA 104: 840-845 [Abstract] [Full Text]  
• Zafonte, B. T., Liu, S., Lynch-Kattman, M., Torregroza, I., Benvenuto, L., Kennedy, M., Keller, G., Evans, T. (2007). Smad1 expands the hemangioblast population within a limited developmental window. Blood 109: 516-523 [Abstract] [Full Text]  
• Blank, U., Karlsson, G., Moody, J. L., Utsugisawa, T., Magnusson, M., Singbrant, S., Larsson, J., Karlsson, S. (2006). Smad7 promotes self-renewal of hematopoietic stem cells. Blood 108: 4246-4254 [Abstract] [Full Text]  
• Singbrant, S., Moody, J. L., Blank, U., Karlsson, G., Umans, L., Zwijsen, A., Karlsson, S. (2006). Smad5 is dispensable for adult murine hematopoiesis. Blood 108: 3707-3712 [Abstract] [Full Text]  
• Tanaka, H., Matsumura, I., Itoh, K., Hatsuyama, A., Shikamura, M., Satoh, Y., Heike, T., Nakahata, T., Kanakura, Y. (2006). HOX Decoy Peptide Enhances the Ex Vivo Expansion of Human Umbilical Cord Blood CD34+ Hematopoietic Stem Cells/Hematopoietic Progenitor Cells. Stem Cells 24: 2592-2602 [Abstract] [Full Text]  
• Chen, X., Xu, H., Wan, C., McCaigue, M., Li, G. (2006). Bioreactor Expansion of Human Adult Bone Marrow-Derived Mesenchymal Stem Cells. Stem Cells 24: 2052-2059 [Abstract] [Full Text]  
• Yeoh, J. S.G., van Os, R., Weersing, E., Ausema, A., Dontje, B., Vellenga, E., de Haan, G. (2006). Fibroblast Growth Factor-1 and -2 Preserve Long-Term Repopulating Ability of Hematopoietic Stem Cells in Serum-Free Cultures. Stem Cells 24: 1564-1572 [Abstract] [Full Text]  
• Gupta, S., Zhu, H., Zon, L. I., Evans, T. (2006). BMP signaling restricts hemato-vascular development from lateral mesoderm during somitogenesis. Development 133: 2177-2187 [Abstract] [Full Text]  
• Utsugisawa, T., Moody, J. L., Aspling, M., Nilsson, E., Carlsson, L., Karlsson, S. (2006). A Road Map Toward Defining the Role of Smad Signaling in Hematopoietic Stem Cells. Stem Cells 24: 1128-1136 [Abstract] [Full Text]  
• Teichert-Kuliszewska, K., Kutryk, M. J.B., Kuliszewski, M. A., Karoubi, G., Courtman, D. W., Zucco, L., Granton, J., Stewart, D. J. (2006). Bone Morphogenetic Protein Receptor-2 Signaling Promotes Pulmonary Arterial Endothelial Cell Survival: Implications for Loss-of-Function Mutations in the Pathogenesis of Pulmonary Hypertension. Circ. Res. 98: 209-217 [Abstract] [Full Text]  
• Langenfeld, E. M., Bojnowski, J., Perone, J., Langenfeld, J. (2005). Expression of Bone Morphogenetic Proteins in Human Lung Carcinomas. Ann. Thorac. Surg. 80: 1028-1032 [Abstract] [Full Text]  
• Wang, X., Hisha, H., Taketani, S., Inaba, M., Li, Q., Cui, W., Song, C., Fan, T., Cui, Y., Guo, K., Yang, G., Fan, H., Lian, Z., Gershwin, M. E., Ikehara, S. (2005). Neural Cell Adhesion Molecule Contributes to Hemopoiesis-Supporting Capacity of Stromal Cell Lines. Stem Cells 23: 1389-1399 [Abstract] [Full Text]  
• Chadwick, K., Shojaei, F., Gallacher, L., Bhatia, M. (2005). Smad7 alters cell fate decisions of human hematopoietic repopulating cells. Blood 105: 1905-1915 [Abstract] [Full Text]  
• Nohe, A., Keating, E., Underhill, T. M., Knaus, P., Petersen, N. O. (2005). Dynamics and interaction of caveolin-1 isoforms with BMP-receptors. J. Cell Sci. 118: 643-650 [Abstract] [Full Text]  
• Martinovic, S., Mazic, S., Kisic, V., Basic, N., Jakic-Razumovic, J., Borovecki, F., Batinic, D., Simic, P., Grgurevic, L., Labar, B., Vukicevic, S. (2004). Expression of Bone Morphogenetic Proteins in Stromal Cells from Human Bone Marrow Long-term Culture. J. Histochem. Cytochem. 52: 1159-1167 [Abstract] [Full Text]  
• Xin, C., Ren, S., Kleuser, B., Shabahang, S., Eberhardt, W., Radeke, H., Schafer-Korting, M., Pfeilschifter, J., Huwiler, A. (2004). Sphingosine 1-Phosphate Cross-activates the Smad Signaling Cascade and Mimics Transforming Growth Factor-{beta}-induced Cell Responses. J. Biol. Chem. 279: 35255-35262 [Abstract] [Full Text]  
• Sadlon, T. J., Lewis, I. D., D'Andrea, R. J. (2004). BMP4: Its Role in Development of the Hematopoietic System and Potential as a Hematopoietic Growth Factor. Stem Cells 22: 457-474 [Abstract] [Full Text]  
• Vas, V., Szilagyi, L., Paloczi, K., Uher, F. (2004). Soluble Jagged-1 is able to inhibit the function of its multivalent form to induce hematopoietic stem cell self-renewal in a surrogate in vitro assay. J. Leukoc. Biol. 75: 714-720 [Abstract] [Full Text]  
• Bond, H. M., Mesuraca, M., Carbone, E., Bonelli, P., Agosti, V., Amodio, N., De Rosa, G., Di Nicola, M., Gianni, A. M., Moore, M. A. S., Hata, A., Grieco, M., Morrone, G., Venuta, S. (2004). Early hematopoietic zinc finger protein (EHZF), the human homolog to mouse Evi3, is highly expressed in primitive human hematopoietic cells. Blood 103: 2062-2070 [Abstract] [Full Text]  
• Larsson, J., Blank, U., Helgadottir, H., Bjornsson, J. M., Ehinger, M., Goumans, M.-J., Fan, X., Leveen, P., Karlsson, S. (2003). TGF-{beta} signaling-deficient hematopoietic stem cells have normal self-renewal and regenerative ability in vivo despite increased proliferative capacity in vitro. Blood 102: 3129-3135 [Abstract] [Full Text]  
• Schmerer, M., Evans, T. (2003). Primitive erythropoiesis is regulated by Smad-dependent signaling in postgastrulation mesoderm. Blood 102: 3196-3205 [Abstract] [Full Text]  
• Nohe, A., Keating, E., Underhill, T. M., Knaus, P., Petersen, N. O. (2003). Effect of the distribution and clustering of the type I A BMP receptor (ALK3) with the type II BMP receptor on the activation of signalling pathways. J. Cell Sci. 116: 3277-3284 [Abstract] [Full Text]  
• Chadwick, K., Wang, L., Li, L., Menendez, P., Murdoch, B., Rouleau, A., Bhatia, M. (2003). Cytokines and BMP-4 promote hematopoietic differentiation of human embryonic stem cells. Blood 102: 906-915 [Abstract] [Full Text]  
• Nagano, M., Ryu, B.-Y., Brinster, C. J., Avarbock, M. R., Brinster, R. L. (2003). Maintenance of Mouse Male Germ Line Stem Cells In Vitro. Biol. Reprod. 68: 2207-2214 [Abstract] [Full Text]  
• Nosaka, T., Morita, S., Kitamura, H., Nakajima, H., Shibata, F., Morikawa, Y., Kataoka, Y., Ebihara, Y., Kawashima, T., Itoh, T., Ozaki, K., Senba, E., Tsuji, K., Makishima, F., Yoshida, N., Kitamura, T. (2003). Mammalian Twisted Gastrulation Is Essential for Skeleto-Lymphogenesis. Mol. Cell. Biol. 23: 2969-2980 [Abstract] [Full Text]  
• Murdoch, B., Chadwick, K., Martin, M., Shojaei, F., Shah, K. V., Gallacher, L., Moon, R. T., Bhatia, M. (2003). Wnt-5A augments repopulating capacity and primitive hematopoietic development of human blood stem cells invivo. Proc. Natl. Acad. Sci. USA 100: 3422-3427 [Abstract] [Full Text]  
• Walters, M. J., Wayman, G. A., Notis, J. C., Goodman, R. H., Soderling, T. R., Christian, J. L. (2003). Calmodulin-dependent protein kinase IV mediated antagonism of BMP signaling regulates lineage and survival of hematopoietic progenitors. Development 129: 1455-1466 [Abstract] [Full Text]  
• Cao, Z., Flanders, K. C., Bertolette, D., Lyakh, L. A., Wurthner, J. U., Parks, W. T., Letterio, J. J., Ruscetti, F. W., Roberts, A. B. (2003). Levels of phospho-Smad2/3 are sensors of the interplay between effects of TGF-beta and retinoic acid on monocytic and granulocytic differentiation of HL-60 cells. Blood 101: 498-507 [Abstract] [Full Text]  
• Hager-Theodorides, A. L., Outram, S. V., Shah, D. K., Sacedon, R., Shrimpton, R. E., Vicente, A., Varas, A., Crompton, T. (2002). Bone Morphogenetic Protein 2/4 Signaling Regulates Early Thymocyte Differentiation. J. Immunol. 169: 5496-5504 [Abstract] [Full Text]  
• Hess, D. A., Levac, K. D., Karanu, F. N., Rosu-Myles, M., White, M. J., Gallacher, L., Murdoch, B., Keeney, M., Ottowski, P., Foley, R., Chin-Yee, I., Bhatia, M. (2002). Functional analysis of human hematopoietic repopulating cells mobilized with granulocyte colony-stimulating factor alone versus granulocyte colony-stimulating factor in combination with stem cell factor. Blood 100: 869-878 [Abstract] [Full Text]  
• Buske, C., Feuring-Buske, M., Abramovich, C., Spiekermann, K., Eaves, C. J., Coulombel, L., Sauvageau, G., Hogge, D. E., Humphries, R. K. (2002). Deregulated expression of HOXB4 enhances the primitive growth activity of human hematopoietic cells. Blood 100: 862-868 [Abstract] [Full Text]  
• Cho, S. K., Bourdeau, A., Letarte, M., Zuniga-Pflucker, J. C. (2001). Expression and function of CD105 during the onset of hematopoiesis from Flk1+ precursors. Blood 98: 3635-3642 [Abstract] [Full Text]  
• Li, F., Lu, S., Vida, L., Thomson, J. A., Honig, G. R. (2001). Bone morphogenetic protein 4 induces efficient hematopoietic differentiation of rhesus monkey embryonic stem cells in vitro. Blood 98: 335-342 [Abstract] [Full Text]  
• Karanu, F. N., Murdoch, B., Miyabayashi, T., Ohno, M., Koremoto, M., Gallacher, L., Wu, D., Itoh, A., Sakano, S., Bhatia, M. (2001). Human homologues of Delta-1 and Delta-4 function as mitogenic regulators of primitive human hematopoietic cells. Blood 97: 1960-1967 [Abstract] [Full Text]  
• Hjertner, O., Hjorth-Hansen, H., Borset, M., Seidel, C., Waage, A., Sundan, A. (2001). Bone morphogenetic protein-4 inhibits proliferation and induces apoptosis of multiple myeloma cells. Blood 97: 516-522 [Abstract] [Full Text]  
• Appelbaum, F. R., Rowe, J. M., Radich, J., Dick, J. E. (2001). Acute Myeloid Leukemia. ASH Education Book 2001: 62-86 [Abstract] [Full Text]  
• Rosu-Myles, M., Gallacher, L., Murdoch, B., Hess, D. A., Keeney, M., Kelvin, D., Dale, L., Ferguson, S. S. G., Wu, D., Fellows, F., Bhatia, M. (2000). The human hematopoietic stem cell compartment is heterogeneous for CXCR4 expression. Proc. Natl. Acad. Sci. USA 97: 14626-14631 [Abstract] [Full Text]  
• Wayman, G. A., Walters, M. J., Kolibaba, K., Soderling, T. R., Christian, J. L. (2000). CaM Kinase IV Regulates Lineage Commitment and Survival of Erythroid Progenitors in a Non-Cell-Autonomous Manner. JCB 151: 811-824 [Abstract] [Full Text]  
• Karanu, F. N., Murdoch, B., Gallacher, L., Wu, D. M., Koremoto, M., Sakano, S., Bhatia, M. (2000). The Notch Ligand Jagged-1 Represents a Novel Growth Factor of Human Hematopoietic Stem Cells. JEM 192: 1365-1372 [Abstract] [Full Text]  
• Kawamura, C., Kizaki, M., Yamato, K., Uchida, H., Fukuchi, Y., Hattori, Y., Koseki, T., Nishihara, T., Ikeda, Y. (2000). Bone morphogenetic protein-2 induces apoptosis in human myeloma cells with modulation of STAT3. Blood 96: 2005-2011 [Abstract] [Full Text]  
• Fortunel, N. O., Hatzfeld, A., Hatzfeld, J. A. (2000). Transforming growth factor-beta : pleiotropic role in the regulation of hematopoiesis. Blood 96: 2022-2036 [Abstract] [Full Text]  
• Rosu-Myles, M., Khandaker, M., Wu, D.M., Keeney, M., Foley, S.R., Howson-Jan, K., Yee, I. C., Fellows, F., Kelvin, D., Bhatia, M. (2000). Characterization of Chemokine Receptors Expressed in Primitive Blood Cells During Human Hematopoietic Ontogeny. Stem Cells 18: 374-381 [Abstract] [Full Text]  
• Gallacher, L., Murdoch, B., Wu, D., Karanu, F., Fellows, F., Bhatia, M. (2000). Identification of novel circulating human embryonic blood stem cells. Blood 96: 1740-1747 [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]  
• Jiang, Y., Liang, H., Guo, W., Kottickal, L. V., Nagarajan, L. (2000). Differential expression of a novel C-terminally truncated splice form of SMAD5 in hematopoietic stem cells and leukemia. Blood 95: 3945-3950 [Abstract] [Full Text]  
• Izumi, M., Fujio, Y., Kunisada, K., Negoro, S., Tone, E., Funamoto, M., Osugi, T., Oshima, Y., Nakaoka, Y., Kishimoto, T., Yamauchi-Takihara, K., Hirota, H. (2001). Bone Morphogenetic Protein-2 Inhibits Serum Deprivation-induced Apoptosis of Neonatal Cardiac Myocytes through Activation of the Smad1 Pathway. J. Biol. Chem. 276: 31133-31141 [Abstract] [Full Text]  

Home | Help | Feedback | Subscriptions | Archive | Search

TABLE OF CONTENTS