Cholinergic signals preserve haematopoietic stem cell quiescence during regenerative haematopoiesis

Claire Fielding, Andrés García-García, Claudia Korn, Stephen Gadomski, Zijian Fang, Juan L. Reguera, José A. Pérez-Simón, Berthold Göttgens and Simón Méndez-Ferrer ()
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Claire Fielding: Wellcome-MRC Cambridge Stem Cell Institute
Andrés García-García: Wellcome-MRC Cambridge Stem Cell Institute
Claudia Korn: Wellcome-MRC Cambridge Stem Cell Institute
Stephen Gadomski: Wellcome-MRC Cambridge Stem Cell Institute
Zijian Fang: Wellcome-MRC Cambridge Stem Cell Institute
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
Berthold Göttgens: Wellcome-MRC Cambridge Stem Cell Institute
Simón Méndez-Ferrer: Wellcome-MRC Cambridge Stem Cell Institute

Nature Communications, 2022, vol. 13, issue 1, 1-13

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-28175-1

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