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

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.

Neuropeptide Y receptor 1 is expressed by B and T lymphocytes and mast cells in infantile haemangiomas

“…This finding suggests a putative role for NPYR1 activation by NPY, resulting in the promotion of microvascular proliferation characteristic of the proliferative phase of IHs, although conclusive evidence for this remains a topic of further investigation. NPY-deficient mice have been shown to exhibit a significantly reduced number of haematopoietic stem cells, as well as impaired regeneration in bone marrow due to apoptotic destruction of sympathetic nervous system fibres and/or endothelial cells (13). Taken together, this suggests that the reduction in NPYR1 + cells during involution demonstrated in this study may, in part, explain the observed increased apoptosis evident in involuted IHs (14).…”

Neuropeptide Y regulates a vascular gateway for hematopoietic stem and progenitor cells

“…A systematic search of protein sequence databases for proteins containing putative CD26 recognition sites intriguingly identified the neurotransmitter NPY (26), a ligand with cognate receptors on monocytes, osteoblasts, stromal cells, and ECs and that has been shown to regulate immune cell and bone homeostasis (27)(28)(29)(30). In addition, recent studies suggest a role for NPY in the regulation of BM niche components and HSPC trafficking (31,32). To test the potential role of CD26-cleaved NPY in regulating HPSC trafficking in response to G-CSF, we first validated by mass spectrometry that CD26 cleaved NPY to the expected truncated NPY 3-36 form ( Figure 5A).…”

Niche heterogeneity in the bone marrow

“…Furthermore, pharmacological elevation of neuropeptide Y prevented the deficits, while neuropeptide Y injection into mice lacking the Y1 receptor specifically in macrophages did not rescue BM dysfunction. 188 …”