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Cholinergic signals preserve haematopoietic stem cell quiescence during regenerative haematopoiesis

Author

Listed:
  • Claire Fielding

    (Wellcome-MRC Cambridge Stem Cell Institute
    University of Cambridge
    Cambridge Biomedical Campus)

  • Andrés García-García

    (Wellcome-MRC Cambridge Stem Cell Institute
    University of Cambridge
    Cambridge Biomedical Campus)

  • Claudia Korn

    (Wellcome-MRC Cambridge Stem Cell Institute
    University of Cambridge
    Cambridge Biomedical Campus)

  • Stephen Gadomski

    (Wellcome-MRC Cambridge Stem Cell Institute
    University of Cambridge
    Cambridge Biomedical Campus
    Skeletal Biology Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Department of Health and Human Services)

  • Zijian Fang

    (Wellcome-MRC Cambridge Stem Cell Institute
    University of Cambridge
    Cambridge Biomedical Campus)

  • Juan L. Reguera

    (University Hospital Virgen del Rocio)

  • José A. Pérez-Simón

    (NIH-Oxford-Cambridge Scholars Program in partnership with Medical University of South Carolina
    University Hospital Virgen del Rocio)

  • Berthold Göttgens

    (Wellcome-MRC Cambridge Stem Cell Institute
    University of Cambridge)

  • Simón Méndez-Ferrer

    (Wellcome-MRC Cambridge Stem Cell Institute
    University of Cambridge
    Cambridge Biomedical Campus
    Instituto de Biomedicina de Sevilla (IBiS/CSIC), Universidad de Sevilla)

Abstract

The sympathetic nervous system has been evolutionary selected to respond to stress and activates haematopoietic stem cells via noradrenergic signals. However, the pathways preserving haematopoietic stem cell quiescence and maintenance under proliferative stress remain largely unknown. Here we found that cholinergic signals preserve haematopoietic stem cell quiescence in bone-associated (endosteal) bone marrow niches. Bone marrow cholinergic neural signals increase during stress haematopoiesis and are amplified through cholinergic osteoprogenitors. Lack of cholinergic innervation impairs balanced responses to chemotherapy or irradiation and reduces haematopoietic stem cell quiescence and self-renewal. Cholinergic signals activate α7 nicotinic receptor in bone marrow mesenchymal stromal cells leading to increased CXCL12 expression and haematopoietic stem cell quiescence. Consequently, nicotine exposure increases endosteal haematopoietic stem cell quiescence in vivo and impairs hematopoietic regeneration after haematopoietic stem cell transplantation in mice. In humans, smoking history is associated with delayed normalisation of platelet counts after allogeneic haematopoietic stem cell transplantation. These results suggest that cholinergic signals preserve stem cell quiescence under proliferative stress.

Suggested Citation

  • Claire Fielding & Andrés García-García & Claudia Korn & Stephen Gadomski & Zijian Fang & Juan L. Reguera & José A. Pérez-Simón & Berthold Göttgens & Simón Méndez-Ferrer, 2022. "Cholinergic signals preserve haematopoietic stem cell quiescence during regenerative haematopoiesis," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-28175-1
    DOI: 10.1038/s41467-022-28175-1
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    References listed on IDEAS

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    1. Simón Méndez-Ferrer & Daniel Lucas & Michela Battista & Paul S. Frenette, 2008. "Haematopoietic stem cell release is regulated by circadian oscillations," Nature, Nature, vol. 452(7186), pages 442-447, March.
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