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Sonic hedgehog induces the proliferation of primitive human hematopoietic cells via BMP regulation

Nature Immunology volume 2, pages 172–180 (2001)Cite this article

Abstract

A pool of stem cells that arise from the mesoderm during embryogenesis initiates hematopoiesis. However, factors that regulate the expansion of blood stem cells are poorly understood. We show here that cytokine-induced proliferation of primitive human hematopoietic cells could be inhibited with antibodies to hedgehog (Hh). Conversely, Sonic hedgehog (Shh) treatment induced the expansion of pluripotent human hematopoietic repopulating cells detected in immunodeficient mice. Noggin, a specific inhibitor of bone morphogenetic protein 4 (BMP-4), was capable of inhibiting Shh-induced proliferation in a similar manner to anti-Hh; however, anti-Hh had no effect on BMP-4–induced proliferation. Our study shows that Shh functions as a regulator of primitive hematopoietic cells via mechanisms that are dependent on downstream BMP signals.

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Figure 1: Expression analysis of the genes encoding Shh, putative receptors and ef-fectors in human hemato-poietic tissue.
Figure 2: Proliferative and clonogenic progenitor capacity of CD34+CD38−Lin− cells after treatment with anti-Hh.
Figure 3: In vitro analysis of primary human CD34+CD38−Lin− cells cultured with human Shh and Dhh proteins.
Figure 4: Analysis of engraftment in NOD-SCID mice with CD34+CD38−Lin− cells cultured in the presence of Hh proteins and anti-Hh.
Figure 5: Regulation of BMP-4 and Noggin expression in primitive human hematopoietic cells.
Figure 6: Functional analysis of Noggin- and Hh-blocking antibodies in response to BMP-4 and Shh in primitive human hematopoietic cells.
Figure 7

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Acknowledgements

We thank the staff of the labor and delivery departments of St. Joseph's Hospital and London Health Sciences, London, Ontario, especially M. Watson and J. Popma, for providing cord blood specimens. We also thank M. Underhill for critically reading the manuscript. Supported by grant MT-15063 from the Medical Research Council (MRC) of Canada and a scholarship award MSH-35681 (to M. B.) also from the MRC.

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Authors and Affiliations

  1. The John P. Robarts Research Institute, Developmental Stem Cell Biology, 100 Perth Drive, London, N6A 5K8, Ontario, Canada

    G. Bhardwaj, B. Murdoch, D. Wu, K. Chadwick, F. N. Karanu & M. Bhatia

  2. Department of Microbiology and Immunology, The University of Western Ontario, Dental Sciences Building, London, N6A 5Cl, Ontario, Canada

    G. Bhardwaj, K. Chadwick & M. Bhatia

  3. Biogen Inc, Boston, 2142, MA, USA

    D. P. Baker, K. P. Williams & L. E. Ling

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Correspondence to M. Bhatia.

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Bhardwaj, G., Murdoch, B., Wu, D. et al. Sonic hedgehog induces the proliferation of primitive human hematopoietic cells via BMP regulation. Nat Immunol 2, 172–180 (2001). https://doi.org/10.1038/84282

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