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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Research Article

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 4

G-CSF treatment increases CD26 expression on BMECs and enhances transendothelial migration of HPCs.

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G-CSF treatment increases CD26 expression on BMECs and enhances transend...
(A) CD26 expression (left and middle) and CD26 proteolytic activity (right) on BM SECs (CD45–Ter119–VEGFR3+VE-cadherin+CD31+) from mice treated with G-CSF or G-CSF plus diprotin A. Positive gates for CD26 expression were based on FMO (green) (mean ± SEM, n = 5 mice/group). (B) Migration of WT and CD26–/– Lin– and LSK cells across G-CSF– or G-CSF plus diprotin A–treated BMEC monolayers to 100 ng/ml SDF-1 (mean ± SEM; n = 2 experiments). (C) Transendothelial migration of LSK cells to 100 ng/ml S1P (mean ± SEM; n = 2 experiments). *P < 0.05 compared with vehicle and †P ≤ 0.05 compared with G-CSF, by Student’s t test (A, left) or 1-way ANOVA with Sidak’s multiple comparisons test (A, right, B and C). V, vehicle; G, G-CSF; G+D, G-CSF plus diprotin A.