2021 - CHOLINERGIC INFLUENCE OF BONE MARROW VASCULAR MICROENVIRONMENT INFLUENCES HEMATOPOIETIC STEM CELL MOBILIZATION

Abstract

The regulation of HSC movement between the bone marrow (BM) microenvironment and the circulation remains an important clinical target in the setting of BM transplantation. The influence of parts of the nervous system, the sympathetic arm in particular, on BM niche function and mobilization have been investigated. However, the basal role of the cholinergic system in regulating HSC mobilisation is yet to be elucidated. We show that the cholinergic system and specifically the nicotinic -7 acetylcholine receptor (Chrna7) mediates alterations in the structure and function of the BM sinusoidal endothelial cells as well as perivascular stromal cells (LepR+). Inhibition of this receptor with MLA leads to a loss of integrity in the BM sinusoidal structures along with a loss in perivascular niche stem cell factor production. Blocking Chrna7 leads to mobilisation of functional HSCs without skewing that is typically present in G-CSF mobilization. This is suggested by single cell RNA sequencing of MLA mobilised peripheral HSCs that indicates a more balanced genetic lineage signature compared to those mobilised with G-CSF. In addition, administering MLA during G-CSF treatment leads to a synergetic effect, while stimulation of the Chrna7 receptor with GTS-21 blunts G-CSF induced HSC mobilisation. These findings suggest a novel role for the peripheral cholinergic system in HSC mobilisation via niche cell alterations that provides a G-CSF independent alternative route for BM transplantation.