Neuropeptide Y regulates the hematopoietic stem cell microenvironment and prevents nerve injury in the bone marrow

• Published in: The EMBO journal 2015-06, Vol.34 (12), p.1648-1660
• Main Authors: Park, Min Hee, Jin, Hee Kyung, Min, Woo-Kie, Lee, Won Woo, Lee, Jeong Eun, Akiyama, Haruhiko, Herzog, Herbert, Enikolopov, Grigori N, Schuchman, Edward H, Bae, Jae-sung
• Format: Article
• Language: English
• Subjects: Analysis of Variance; Animals; Apoptosis - physiology; Bone marrow; Bone Marrow - physiology; Bone Marrow Cells - metabolism; bone marrow microenvironment; Cellular Microenvironment - physiology; Chemotherapy; EMBO27; EMBO37; EMBO39; Endothelial Cells - physiology; Fibers; Flow Cytometry; Fluorescent Antibody Technique; hematopoietic stem cell; Hematopoietic Stem Cells - metabolism; Hematopoietic Stem Cells - physiology; Mice; Mice, Knockout; Nerve Fibers, Myelinated - metabolism; neuropeptide Y; Neuropeptide Y - deficiency; Neuropeptide Y - metabolism; Neuropeptides; regeneration; Rodents; Stem cells; sympathetic nervous system; Sympathetic Nervous System - cytology; Transplants & implants
• ISSN: 0261-4189; 1460-2075
• DOI: 10.15252/embj.201490174

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. Synopsis Neuropeptide Y maintains hematopoietic stem cells in the bone marrow by instructing the stromal microenvironment. NPY deficiency causes impairment of HSC survival and bone marrow regeneration. Bone marrow dysfunction by NPY deficiency is due to the destruction of SNS nerve fibers and/or EC reduction. NPY mediates Y1 receptor activation in macrophages, contributing in turn to HSC survival. Treatment with NPY or Y1 agonists prevents cisplatin‐induced bone marrow nerve injury. Graphical Abstract Neuropeptide Y maintains hematopoietic stem cells in the bone marrow by instructing the stromal microenvironment.