Loss of Adrenergic Nerves in the Bone Marrow Microenvironment Drives an Aging HSC Niche Phenotype

Hematopoietic stem cell (HSC) aging is accompanied by an expansion of myeloid-biased HSCs with declined long-term self-renewal functions, contributing to the development of hematologic malignancies. Recent studies have suggested a role for the bone marrow microenvironment in HSC aging but the extrinsic molecular mechanisms driving their aging remain largely unknown. Mesenchymal stem cells (MSCs) form a critical component of the HSC niche, promoting HSC quiescence and balanced differentiation. Some MSC activity is found associated with arterioles, which are densely innervated by the sympathetic nervous system (SNS). We used tridimensional whole-mount bone marrow confocal immunofluorescence imaging of HSCs and vascular structures to investigate the effects of aging on the HSC microenvironment. Comparative bone marrow analyses of aged (20-24 months) C57BL/6 and Nestin-GFP transgenic mice (where GFP marks MSCs) with young (2 month-old) C57BL/6 mice, revealed significant reductions in sympathetic innervation (3-fold, p Disclosures Frenette:Pfizer: Consultancy; GSK: Research Funding; PHD Biosciences: Research Funding.