Cholinergic signals promote the quiescence of normal or leukaemic stem cells through the activation of the α7-nicotinic receptor in bone marrow mesenchymal stromal cells

The sympathetic nervous system has evolved to respond to stress and activates haematopoietic stem cells (HSCs) using noradrenergic signals. However, the pathways that maintain HSC quiescence and maintenance during proliferative stress are not well understood. This study has investigated the role of cholinergic signals during healthy and malignant haematopoiesis. During healthy haematopoiesis, sympathetic cholinergic signals maintain HSC quiescence in bone-associated (endosteal) bone marrow (BM) niches. During stress haematopoiesis, cholinergic neural signals increase and are amplified through cholinergic osteoprogenitors. If cholinergic innervation is absent, responses to chemotherapy or irradiation become unbalanced and HSC quiescence and self-renewal decrease. Cholinergic signals activate the α7 nicotinic receptor in BM mesenchymal stromal cells (BMSCs), leading to increased CXCL12 expression and HSC quiescence. In vivo, exposure to nicotine increases endosteal HSC quiescence and impairs haematopoietic regeneration after HSC transplantation in mice. In acute myeloid leukaemia (AML), cholinergic fibres are preserved despite a decrease in sympathetic noradrenergic innervation. Loss of sympathetic cholinergic innervation or α7 nicotinic acetylcholine receptor (α7nAChR) signalling in the BM microenvironment promotes HSPC proliferation and accelerates leukaemogenesis. Blockade of peripheral α7nAChR renders chemoresistant quiescent AML cells sensitive to induction chemotherapy and shows synergistic therapeutic effects in the AML model in vivo. These results suggest that the cholinergic system has a regenerative function in healthy haematopoiesis and could be a promising target to boost induction chemotherapy’s efficacy in AML.

Name dc:type.qualificationname

Doctor of Philosophy (PhD)

Level dc:type.qualificationlevel

Doctoral

Grantor dc:publisher.institution

University of Cambridge

Year dc:date.issued

2023

Author dc:creator

• Fielding, Claire

Advisor dc:contributor.advisor

• Mendez-Ferrer, Simon

• Haematology
• Haematological malignancies
• Cholinergic
• Neuronal regulation
• AML
• Bone marrow stem cell niche

Licence

• https://www.repository.cam.ac.uk/bitstreams/e866d05a-e1ed-4492-92ff-f8fa994bded8/download
• https://www.rioxx.net/licenses/all-rights-reserved/

Language dc:language

eng

Author Identifier

0000-0002-5984-9127

OAI identifier oai:identifier

oai:www.repository.cam.ac.uk:1810/353883