Cholinergic signals preserve haematopoietic stem cell quiescence during regenerative haematopoiesis.
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Authors
Fielding, Claire
Korn, Claudia
Gadomski, Stephen
Fang, Zijian
Reguera, Juan L
Publication Date
2022-01-27Journal Title
Nat Commun
ISSN
2041-1723
Publisher
Nature Research
Volume
13
Issue
1
Language
eng
Type
Article
This Version
VoR
Metadata
Show full item recordCitation
Fielding, C., García-García, A., Korn, C., Gadomski, S., Fang, Z., Reguera, J. L., Pérez-Simón, J. A., et al. (2022). Cholinergic signals preserve haematopoietic stem cell quiescence during regenerative haematopoiesis.. Nat Commun, 13 (1) https://doi.org/10.1038/s41467-022-28175-1
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.
Keywords
Hematopoietic Stem Cells, Mesenchymal Stem Cells, Bone Marrow, Animals, Humans, Mice, Receptors, Adrenergic, beta-3, Cholinergic Agents, Hematopoietic Stem Cell Transplantation, Risk Factors, Hematopoiesis, Glial Cell Line-Derived Neurotrophic Factor Receptors, Chemokine CXCL12
Sponsorship
Wellcome Trust (203151/Z/16/Z)
Wellcome Trust (203151/A/16/Z)
European Research Council (648765)
MRC (MR/V005421/1)
Cancer Research UK (CRUK-)
Medical Research Council (G0900951)
Medical Research Council (MR/S036113/1)
Medical Research Council (MC_PC_17230)
Identifiers
PMC8795384, 35087060
External DOI: https://doi.org/10.1038/s41467-022-28175-1
This record's URL: https://www.repository.cam.ac.uk/handle/1810/334532
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