Neuropeptide Y regulates a vascular gateway for hematopoietic stem and progenitor cells
Pratibha Singh, … , Theresa A. Guise, Louis M. Pelus
Pratibha Singh, … , Theresa A. Guise, Louis M. Pelus
Published November 13, 2017
Citation Information: J Clin Invest. 2017;127(12):4527-4540. https://doi.org/10.1172/JCI94687.
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Neuropeptide Y regulates a vascular gateway for hematopoietic stem and progenitor cells

Abstract

Endothelial cells (ECs) are components of the hematopoietic microenvironment and regulate hematopoietic stem and progenitor cell (HSPC) homeostasis. Cytokine treatments that cause HSPC trafficking to peripheral blood are associated with an increase in dipeptidylpeptidase 4/CD26 (DPP4/CD26), an enzyme that truncates the neurotransmitter neuropeptide Y (NPY). Here, we show that enzymatically altered NPY signaling in ECs caused reduced VE-cadherin and CD31 expression along EC junctions, resulting in increased vascular permeability and HSPC egress. Moreover, selective NPY2 and NPY5 receptor antagonists restored vascular integrity and limited HSPC mobilization, demonstrating that the enzymatically controlled vascular gateway specifically opens by cleavage of NPY by CD26 signaling via NPY2 and NPY5 receptors. Mice lacking CD26 or NPY exhibited impaired HSPC trafficking that was restored by treatment with truncated NPY. Thus, our results point to ECs as gatekeepers of HSPC trafficking and identify a CD26-mediated NPY axis that has potential as a pharmacologic target to regulate hematopoietic trafficking in homeostatic and stress conditions.

Authors

Pratibha Singh, Jonathan Hoggatt, Malgorzata M. Kamocka, Khalid S. Mohammad, Mary R. Saunders, Hongge Li, Jennifer Speth, Nadia Carlesso, Theresa A. Guise, Louis M. Pelus

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Figure 3

G-CSF treatment does not induce proteolytic degradation of SDF-1 in BM.

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G-CSF treatment does not induce proteolytic degradation of SDF-1 in BM. ...
(A) Left: Mass spectroscopic analysis shows cleavage of SDF-1 exclusively to SDF-13-68. Middle: Intact and DPP4-cleaved SDF-1 binding to Jurkat cell CXCR4 receptors (mean ± SEM; n = 3 experiments). Right: Dose response analysis of intact and DPP4-cleaved SDF-1binding to Jurkat CXCR4. (B) Receptor binding efficiency of BMEF SDF-1 from G-CSF– or G-CSF plus diprotin A–treated mice. Bound SDF-1 was detected by anti–SDF-1 antibody staining and flow cytometry (mean ± SEM; 3 mice/group; n = 3 experiments). (C and D) Effect of G-CSF or G-CSF plus diprotin A treatment on levels of membrane-associated SDF-1 on BM LSK cells (C) and CD45–CD119– stromal cells (D). BM cells were isolated by flushing femurs with PBS and stained with lineage-specific cell-surface antibodies and anti–SDF-1 antibody. Positive gates were based on fluorescence minus 1 (FMO) (green) (mean ± SEM; n = 5 mice/group). *P ≤ 0.05 compared with vehicle using 1-way ANOVA with Sidak’s multiple comparisons test.