Min Hee Park1,2,3,†, Hee Kyung Jin1,4,†, Woo-Kie Min5, Won Woo Lee6, Jeong Eun Lee7, Haruhiko Akiyama8, Herbert Herzog9, Grigori N Enikolopov10, Edward H Schuchman11 and Jae-sung Bae*,1,2,3
1Stem Cell Neuroplasticity Research Group, Kyungpook National University, Daegu, Korea
2Department of Physiology, Cell and Matrix Research Institute, School of Medicine, Kyungpook National University, Daegu, Korea
3Department of Biomedical Science, BK21 Plus KNU Biomedical Convergence Program, Kyungpook National University, Daegu, Korea
4Department of Laboratory Animal Medicine, College of Veterinary Medicine, Kyungpook National University, Daegu, Korea
5Department of Orthopaedic Surgery, Kyungpook National University Hospital, Daegu, Korea
6Department of Microbiology and Immunology, Seoul National University College of Medicine, Seoul, Korea
7Department of Radiation Oncology, Kyungpook National University Hospital, Daegu, Korea
8Department of Orthopaedics, Kyoto University, Kyoto, Japan
9Neuroscience Research Program, Garvan Institute of Medical Research, Sydney, NSW, Australia
10Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, NY, USA
11Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
*Corresponding author : Jae-sung Bae
† These authors contributed equally to this work
Abstract
Many reports have revealed the importance of the sympathetic nervous system (SNS) in the control of the bone marrow environment. However, the specific role of neuropeptide Y (NPY) in this process has not been systematically studied. Here we show that NPY-deficient mice have significantly reduced hematopoietic stem cell (HSC) numbers and impaired regeneration in bone marrow due to apoptotic destruction of SNS fibers and/or endothelial cells. Furthermore, pharmacological elevation of NPY prevented bone marrow impairments in a mouse model of chemotherapy-induced SNS injury, while NPY injection into conditional knockout mice lacking the Y1 receptor in macrophages did not relieve bone marrow dysfunction. These results indicate that NPY promotes neuroprotection and restores bone marrow dysfunction from chemotherapy-induced SNS injury through the Y1 receptor in macrophages. They also reveal a new role of NPY as a regulator of the bone marrow microenvironment and highlight the potential therapeutic value of this neuropeptide.