Neuropeptide Y Regulates a Vascular Gateway for Hematopoietic Stem and Progenitor Cells

Overview

Journal J Clin Invest

Specialty General Medicine

Date 2017 Nov 14

PMID 29130940

Citations 23

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

Affiliations

Soon will be listed here.

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.

Citing Articles

Systemic and local regulation of hematopoietic homeostasis in health and disease.

Carpenter R, Maryanovich M Nat Cardiovasc Res. 2024; 3(6):651-665.

PMID: 39196230 DOI: 10.1038/s44161-024-00482-4.

Role of Neurotransmitters in Steady State Hematopoiesis, Aging, and Leukemia.

Beeraka N, Basappa B, Nikolenko V, Mahesh P Stem Cell Rev Rep. 2024; 21(1):2-27.

PMID: 38976142 DOI: 10.1007/s12015-024-10761-z.

Platelet-derived circulating soluble P-selectin is sufficient to induce hematopoietic stem cell mobilization.

Wang T, Liou Y, Yang S, Lin G, Chiang Y, Lien T Stem Cell Res Ther. 2023; 14(1):300.

PMID: 37864264 PMC: 10589967. DOI: 10.1186/s13287-023-03527-w.

Hematopoietic stem cell mobilization.

Chang H, Liou Y, Sun D Tzu Chi Med J. 2022; 34(3):270-275.

PMID: 35912054 PMC: 9333105. DOI: 10.4103/tcmj.tcmj_98_21.

Neuropeptide Y: An Update on the Mechanism Underlying Chronic Intermittent Hypoxia-Induced Endothelial Dysfunction.

Li M, Zheng Y, Wang W, Lin S, Lin H Front Physiol. 2021; 12:712281.

PMID: 34512386 PMC: 8430344. DOI: 10.3389/fphys.2021.712281.

References

Park M, Lee J, Kim N, Min W, Lee J, Kim K . Neuropeptide Y Induces Hematopoietic Stem/Progenitor Cell Mobilization by Regulating Matrix Metalloproteinase-9 Activity Through Y1 Receptor in Osteoblasts. Stem Cells. 2016; 34(8):2145-56. DOI: 10.1002/stem.2383. View

Lambeir A, Proost P, Durinx C, Bal G, Senten K, Augustyns K . Kinetic investigation of chemokine truncation by CD26/dipeptidyl peptidase IV reveals a striking selectivity within the chemokine family. J Biol Chem. 2001; 276(32):29839-45. DOI: 10.1074/jbc.M103106200. View

Proost P, Struyf S, Schols D, Durinx C, Wuyts A, Lenaerts J . Processing by CD26/dipeptidyl-peptidase IV reduces the chemotactic and anti-HIV-1 activity of stromal-cell-derived factor-1alpha. FEBS Lett. 1998; 432(1-2):73-6. DOI: 10.1016/s0014-5793(98)00830-8. View

Smith-Berdan S, Nguyen A, Hong M, Forsberg E . ROBO4-mediated vascular integrity regulates the directionality of hematopoietic stem cell trafficking. Stem Cell Reports. 2015; 4(2):255-68. PMC: 4325232. DOI: 10.1016/j.stemcr.2014.12.013. View

Christopherson 2nd K, Cooper S, Broxmeyer H . Cell surface peptidase CD26/DPPIV mediates G-CSF mobilization of mouse progenitor cells. Blood. 2003; 101(12):4680-6. DOI: 10.1182/blood-2002-12-3893. View

Mentlein R, DAHMS P, Grandt D, Kruger R . Proteolytic processing of neuropeptide Y and peptide YY by dipeptidyl peptidase IV. Regul Pept. 1993; 49(2):133-44. DOI: 10.1016/0167-0115(93)90435-b. View

Chen J, Miyanishi M, Wang S, Yamazaki S, Sinha R, Kao K . Hoxb5 marks long-term haematopoietic stem cells and reveals a homogenous perivascular niche. Nature. 2016; 530(7589):223-7. PMC: 4854608. DOI: 10.1038/nature16943. View

Mentlein R . Dipeptidyl-peptidase IV (CD26)--role in the inactivation of regulatory peptides. Regul Pept. 1999; 85(1):9-24. DOI: 10.1016/s0167-0115(99)00089-0. View

Ding L, Saunders T, Enikolopov G, Morrison S . Endothelial and perivascular cells maintain haematopoietic stem cells. Nature. 2012; 481(7382):457-62. PMC: 3270376. DOI: 10.1038/nature10783. View

10.

Christopherson 2nd K, Hangoc G, Broxmeyer H . Cell surface peptidase CD26/dipeptidylpeptidase IV regulates CXCL12/stromal cell-derived factor-1 alpha-mediated chemotaxis of human cord blood CD34+ progenitor cells. J Immunol. 2002; 169(12):7000-8. DOI: 10.4049/jimmunol.169.12.7000. View

11.

Ou X, OLeary H, Broxmeyer H . Implications of DPP4 modification of proteins that regulate stem/progenitor and more mature cell types. Blood. 2013; 122(2):161-9. PMC: 3709652. DOI: 10.1182/blood-2013-02-487470. View

12.

Heissig B, Hattori K, Dias S, Friedrich M, Ferris B, Hackett N . Recruitment of stem and progenitor cells from the bone marrow niche requires MMP-9 mediated release of kit-ligand. Cell. 2002; 109(5):625-37. PMC: 2826110. DOI: 10.1016/s0092-8674(02)00754-7. View

13.

Broxmeyer H, Hoggatt J, OLeary H, Mantel C, Chitteti B, Cooper S . Dipeptidylpeptidase 4 negatively regulates colony-stimulating factor activity and stress hematopoiesis. Nat Med. 2012; 18(12):1786-96. PMC: 3742313. DOI: 10.1038/nm.2991. View

14.

Gavard J, Gutkind J . VEGF controls endothelial-cell permeability by promoting the beta-arrestin-dependent endocytosis of VE-cadherin. Nat Cell Biol. 2006; 8(11):1223-34. DOI: 10.1038/ncb1486. View

15.

Privratsky J, Paddock C, Florey O, Newman D, Muller W, Newman P . Relative contribution of PECAM-1 adhesion and signaling to the maintenance of vascular integrity. J Cell Sci. 2011; 124(Pt 9):1477-85. PMC: 3078814. DOI: 10.1242/jcs.082271. View

16.

Ekblad E, Edvinsson L, Wahlestedt C, Uddman R, Hakanson R, Sundler F . Neuropeptide Y co-exists and co-operates with noradrenaline in perivascular nerve fibers. Regul Pept. 1984; 8(3):225-35. DOI: 10.1016/0167-0115(84)90064-8. View

17.

Dar A, Goichberg P, Shinder V, Kalinkovich A, Kollet O, Netzer N . Chemokine receptor CXCR4-dependent internalization and resecretion of functional chemokine SDF-1 by bone marrow endothelial and stromal cells. Nat Immunol. 2005; 6(10):1038-46. DOI: 10.1038/ni1251. View

18.

Nakamura Y, Arai F, Iwasaki H, Hosokawa K, Kobayashi I, Gomei Y . Isolation and characterization of endosteal niche cell populations that regulate hematopoietic stem cells. Blood. 2010; 116(9):1422-32. DOI: 10.1182/blood-2009-08-239194. View

19.

Hoggatt J, Speth J, Pelus L . Concise review: Sowing the seeds of a fruitful harvest: hematopoietic stem cell mobilization. Stem Cells. 2013; 31(12):2599-606. PMC: 3947455. DOI: 10.1002/stem.1574. View

20.

Mendez-Ferrer S, Michurina T, Ferraro F, Mazloom A, MacArthur B, Lira S . Mesenchymal and haematopoietic stem cells form a unique bone marrow niche. Nature. 2010; 466(7308):829-34. PMC: 3146551. DOI: 10.1038/nature09262. View