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Cholinergic signals preserve haematopoietic stem cell quiescence during regenerative haematopoiesis.

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Fielding, Claire 
García-García, Andrés  ORCID logo
Korn, Claudia 
Gadomski, Stephen 
Fang, Zijian 


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.



Animals, Bone Marrow, Chemokine CXCL12, Cholinergic Agents, Glial Cell Line-Derived Neurotrophic Factor Receptors, Hematopoiesis, Hematopoietic Stem Cell Transplantation, Hematopoietic Stem Cells, Humans, Mesenchymal Stem Cells, Mice, Receptors, Adrenergic, beta-3, Risk Factors

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Nat Commun

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Nature Research
Wellcome Trust (203151/Z/16/Z)
Wellcome Trust (203151/A/16/Z)
European Research Council (648765)
MRC (MR/V005421/1)
Cancer Research UK (C61367/A26670)
Medical Research Council (G0900951)
Medical Research Council (MR/S036113/1)
Medical Research Council (MC_PC_17230)
Medical Research Council (G0900951/1)
Cancer Research UK (26670)