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Osteoblastic cells regulate the haematopoietic stem cell niche

Author

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  • L. M. Calvi

    (Center for Human Genetics and Molecular Pediatric Disease, University of Rochester School of Medicine)

  • G. B. Adams

    (Center for Regenerative Medicine and Technology, Partners AIDS Research Center, MGH Cancer Center, Massachusetts General Hospital, Harvard Medical School)

  • K. W. Weibrecht

    (Center for Regenerative Medicine and Technology, Partners AIDS Research Center, MGH Cancer Center, Massachusetts General Hospital, Harvard Medical School)

  • J. M. Weber

    (Center for Human Genetics and Molecular Pediatric Disease, University of Rochester School of Medicine)

  • D. P. Olson

    (Center for Regenerative Medicine and Technology, Partners AIDS Research Center, MGH Cancer Center, Massachusetts General Hospital, Harvard Medical School)

  • M. C. Knight

    (Massachusetts General Hospital, Harvard Medical School)

  • R. P. Martin

    (Center for Regenerative Medicine and Technology, Partners AIDS Research Center, MGH Cancer Center, Massachusetts General Hospital, Harvard Medical School)

  • E. Schipani

    (Massachusetts General Hospital, Harvard Medical School)

  • P. Divieti

    (Massachusetts General Hospital, Harvard Medical School)

  • F. R. Bringhurst

    (Massachusetts General Hospital, Harvard Medical School)

  • L. A. Milner

    (University of Rochester School of Medicine)

  • H. M. Kronenberg

    (Massachusetts General Hospital, Harvard Medical School)

  • D. T. Scadden

    (Center for Regenerative Medicine and Technology, Partners AIDS Research Center, MGH Cancer Center, Massachusetts General Hospital, Harvard Medical School)

Abstract

Stem cell fate is influenced by specialized microenvironments that remain poorly defined in mammals1,2,3. To explore the possibility that haematopoietic stem cells derive regulatory information from bone, accounting for the localization of haematopoiesis in bone marrow, we assessed mice that were genetically altered to produce osteoblast-specific, activated PTH/PTHrP receptors (PPRs)4. Here we show that PPR-stimulated osteoblastic cells that are increased in number produce high levels of the Notch ligand jagged 1 and support an increase in the number of haematopoietic stem cells with evidence of Notch1 activation in vivo. Furthermore, ligand-dependent activation of PPR with parathyroid hormone (PTH) increased the number of osteoblasts in stromal cultures, and augmented ex vivo primitive haematopoietic cell growth that was abrogated by γ-secretase inhibition of Notch activation. An increase in the number of stem cells was observed in wild-type animals after PTH injection, and survival after bone marrow transplantation was markedly improved. Therefore, osteoblastic cells are a regulatory component of the haematopoietic stem cell niche in vivo that influences stem cell function through Notch activation. Niche constituent cells or signalling pathways provide pharmacological targets with therapeutic potential for stem-cell-based therapies.

Suggested Citation

  • L. M. Calvi & G. B. Adams & K. W. Weibrecht & J. M. Weber & D. P. Olson & M. C. Knight & R. P. Martin & E. Schipani & P. Divieti & F. R. Bringhurst & L. A. Milner & H. M. Kronenberg & D. T. Scadden, 2003. "Osteoblastic cells regulate the haematopoietic stem cell niche," Nature, Nature, vol. 425(6960), pages 841-846, October.
    • Handle: RePEc:nat:nature:v:425:y:2003:i:6960:d:10.1038_nature02040
    DOI: 10.1038/nature02040
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    Cited by:

    1. Géraldine Poncin & Aurore Beaulieu & Chantal Humblet & Albert Thiry & Kimimitsu Oda & Jacques Boniver & Marie-Paule Defresne, 2012. "Characterization of Spontaneous Bone Marrow Recovery after Sublethal Total Body Irradiation: Importance of the Osteoblastic/Adipocytic Balance," PLOS ONE, Public Library of Science, vol. 7(2), pages 1-13, February.
    2. Adrienne Anginot & Julie Nguyen & Zeina Abou Nader & Vincent Rondeau & Amélie Bonaud & Maria Kalogeraki & Antoine Boutin & Julia P. Lemos & Valeria Bisio & Joyce Koenen & Lea Hanna Doumit Sakr & Amand, 2023. "WHIM Syndrome-linked CXCR4 mutations drive osteoporosis," Nature Communications, Nature, vol. 14(1), pages 1-20, December.
    3. Xue Zhong & Nagesh Peddada & Jianhui Wang & James J. Moresco & Xiaowei Zhan & John M. Shelton & Jeffrey A. SoRelle & Katie Keller & Danielle Renee Lazaro & Eva Marie Y. Moresco & Jin Huk Choi & Bruce , 2023. "OVOL2 sustains postnatal thymic epithelial cell identity," Nature Communications, Nature, vol. 14(1), pages 1-22, December.

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