Skip to main content
SpringerLink
Log in

P-selectin glycoprotein ligand-1 deficiency augments G-CSF induced myeloid cell mobilization

  • Original Article
  • Published:
Naunyn-Schmiedeberg's Archives of Pharmacology Aims and scope Submit manuscript

Abstract

The effect of granulocyte colony-stimulating factor (G-CSF) was investigated in P-selectin glycoprotein ligand-1 (PSGL-1) deficient (PSGL-1−/−) and wild-type (PSGL-1+/+) mice to establish the role of this mucin in myeloid cell mobilization. G-CSF activates tissue proteases that cleave adhesion molecules, thus enhances the mobilization of myeloid cells and haematopoietic stem cells. Cytopenia was induced with a single dose of cyclophosphamide. In PSGL-1−/− animals, we observed a delayed extravasation of mature myeloid cells from the peripheral vessels into the tissue compartments and their faster mobilization from the bone marrow. Subsequently, animals received G-CSF twice a day for 4 days. Neutrophil and monocyte counts increased upon completion of G-CSF treatment and both values were significantly higher in PSGL-1−/− mice; 47.7 versus 28.3 G/l for neutrophils and 4.1 versus 2.0 G/l for monocytes. The ratio of atypical myeloid cells was also elevated. Analyzing the causes of the above differences, we identified a 4-fold increase in the colony-forming unit (CFU-GM) counts of the peripheral blood in PSGL-1−/− mice, compared to wild-type animals. A significantly elevated number of CFU-GM was detected also in the femurs of PSGL-1−/− mice, 4 and 5 days after cyclophosphamide treatment and these values paralleled with the elevation of CD34+/CD117+ stem cell counts in the peripheral blood. Our data suggest, that in the absence of PSGL-1, G-CSF was more potent in elevating absolute myeloid cell numbers by acting on cell release from the bone marrow, maturation from circulating precursor cells in the peripheral blood and prolonged retainment in the circulation.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

Abbreviations

ABC:

Antibody binding capacity

ACD:

Acid citrate dextrose

CFU-GM:

Colony-forming unit granulocyte/macrophage

CXCR4:

Chemokine C-X-C motif receptor 4

FITC:

Fluorescein isothiocyanate

G-CSF:

Granulocyte colony-stimulating factor

GM-CSF:

Granulocyte–macrophage colony-stimulating factor

HSC:

Hematopoietic stem cells

IHC:

Immunohistochemical reaction

IL:

Interleukin

MFI:

Mean fluorescence intensity

PSGL-1:

P-selectin glycoprotein ligand-1

R-PE:

R-Phycoerythrin

SDF-1:

Stromal cell-derived factor 1

VCAM-1:

Vascular cell adhesion molecule-1

References

  • Benko I, Hernádi F, Megyeri A, Kiss A, Somogyi G, Tegyey Z, Kraicsovits F, Kovács P (1999) Comparison of the toxicity of fluconazole and other azole antifungal drugs to murine and human granulocyte–macrophage progenitor cells in vitro. J Antimicrob Chemother 43:675–681

    Article  CAS  PubMed  Google Scholar 

  • Benko I, Kovács P, Szegedi I, Megyeri A, Kiss A, Balogh E, Oláh E, Kappelmayer J, Kiss C (2001) Effect of myelopoietic and pleiotropic cytokines on colony formation by blast cells of children with acute lymphoblastic leukemia. Naunyn Schmiedebergs Arch Pharmacol 363:499–508

    Article  CAS  PubMed  Google Scholar 

  • Broxmeyer HE, Orschell CM, Clapp DW, Hangoc G, Cooper S, Plett PA, Liles WC, Li X, Graham-Evans B, Campbell TB, Calandra G, Bridger G, Dale DC, Srour EF (2005) Rapid mobilization of murine and human hematopoietic stem and progenitor cells with AMD3100, a CXCR4 antagonist. J Exp Med 201:1307–1318

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Cline MJ, Golde DW (1977) Mobilization of hematopoietic stem cells (CFU-C) into the peripheral blood of man by endotoxin. Exp Hematol 3:186–190

    Google Scholar 

  • Davenpeck KL, Brummet ME, Hudson SA, Mayer RJ, Bochner BS (2000) Activation of human leukocytes reduces surface P-selectin glycoprotein ligand-1 (PSGL-1, CD162) and adhesion to P-selectin in vitro. J Immun 165:2764–2772

    CAS  PubMed  Google Scholar 

  • De Haan G, Ausema A, Wilkens M, Molineux G, Dontje B (2000) Efficient mobilization of haematopoietic progenitors after a single injection of pegylated recombinant human granulocyte colony-stimulating factor in mouse strains with distinct marrow-cell pool sizes. Br J Haematol 110:638–646

    Article  PubMed  Google Scholar 

  • Dugan MJ, Maziarz RT, Bensinger WI, Nademanee A, Liesveld J, Badel K, Dehner C, Gibney C, Bridger G, Calandra G (2010) Safety and preliminary efficacy of plerixafor (Mozobil) in combination with chemotherapy and G-CSF: An open-label, multicenter, exploratory trial in patients with multiple myeloma and non-Hodgkin's lymphoma undergoing stem cell mobilization. Bone Marrow Transplant 45:39–47

    Article  CAS  PubMed  Google Scholar 

  • Elghetany MT (2002) Surface antigen changes during normal neutrophilic development: A critical review. Blood Cells Mol Dis 28:260–274

    Article  PubMed  Google Scholar 

  • Ellefson DD, diZerega GS, Espinoza T, Roda N, Maldonado S, Rodgers KE (2004) Synergistic effects of co-administration of angiotensin 1–7 and Neupogen on hematopoietic recovery in mice. Cancer Chemother Pharmacol 53:15–24

    CAS  PubMed  Google Scholar 

  • Eto T, Winkler I, Purton LE, Lévesque JP (2005) Contrasting effects of P-selectin and E-selectin on the differentiation of murine hematopoietic progenitor cells. Exp Hematol 33:232–242

    Article  CAS  PubMed  Google Scholar 

  • Fenk R, Hieronimus N, Steidl U, Bruns I, Graef T, Zohren F, Ruf L, Haas R, Kobbe G (2006) Sustained G-CSF plasma levels following administration of pegfilgrastim fasten neutrophil reconstitution after high-dose chemotherapy and autologous blood stem cell transplantation in patients with multiple myeloma. Exp Hematol 34:1296–1302

    Article  CAS  PubMed  Google Scholar 

  • Figueiredo J, Ferreira AE, Silva RL, Ulloa L, Grieco P, Cunha TM, Ferreira SH, Cunha FD, Kanashiro A (2013) NDP-MSH inhibits neutrophil migration through nicotinic and adrenergic receptors in experimental peritonitis. Naunyn-Schmiedebergs Arch Pharmacol 386:311–318

    Article  CAS  PubMed  Google Scholar 

  • Frenette PS, Weiss L (2000) Sulfated glycans induce rapid hematopoietic progenitor cell mobilization: Evidence for selectin-dependent and independent mechanisms. Blood 96:2460–2468

    CAS  PubMed  Google Scholar 

  • Géresi K, Benkő K, Szabó B, Megyeri A, Peitl B, Szilvássy Z, Benkő I (2012) Toxicity of cytotoxic agents to granulocyte–macrophage progenitors is increased in obese Zucker and non-obese but insulin resistant Goto–Kakizaki rats. Eur J Pharmacol 696:172–178

    Article  PubMed  Google Scholar 

  • Gertz MA (2010) Current status of stem cell mobilization. Br J Haematol 150:647–662

    Article  CAS  PubMed  Google Scholar 

  • Goodman JW, Hodgson GS (1962) Evidence for stem cells in the peripheral blood of mice. Blood 19:702–714

    CAS  PubMed  Google Scholar 

  • Jilma B, Hergovich N, Homoncik M, Marsik C, Kreuzer C, Jilma-Stohlawetz P (2002) Rapid down-modulation of P-seelectin glycoprotein ligand-1 (PSGL-1, CD162) by G-CSF in humans. Transfusion 42:328–333

    Article  CAS  PubMed  Google Scholar 

  • Kappelmayer J, Kiss A, Karászi É, Veszprémi A, Jakó J, Cs K (2001) Identification of P-selectin glycoprotein ligand-1 as a useful marker in acute myeloid leukaemias. Br J Haematol 115:903–909

    Article  CAS  PubMed  Google Scholar 

  • Kappelmayer J, Nagy B Jr, Miszti-Blasius K, Hevessy Z, Setiadi H (2004) The emerging value of P-selectin as a disease marker. Clin Chem Lab Med 42:475–486

    Article  CAS  PubMed  Google Scholar 

  • Lane TA, Law P, Maruyama M, Young D, Burgess J, Mullen M, Mealiffe M, Terstappen LW, Hardwick A, Moubayed M et al (1995) Harvesting and enrichment of hematopoietic progenitor cells mobilized into the peripheral blood of normal donors by granulocyte–macrophage colony-stimulating factor (GM-CSF) or G-CSF: Potential role in allogeneic marrow transplantation. Blood 85:275–282

    CAS  PubMed  Google Scholar 

  • Laszik Z, Jansen PJ, Cummings RD, Tedder TF, McEver RP, Moore KL (1996) P-selectin glycoprotein ligand-1 is broadly expressed in cells of myeloid, lymphoid, and dendritic lineage and in some nonhematopoietic cells. Blood 88:3010–3021

    CAS  PubMed  Google Scholar 

  • Lévesque JP, Zannettino AC, Pudney M, Niutta S, Haylock DN, Snapp KR, Kansas GS, Berndt MC, Simmons PJ (1999) PSGL-1 mediated adhesion of human hematopoietic progenitors to P-selectin results in suppression of hematopoiesis. Immunity 11:369–378

    Article  PubMed  Google Scholar 

  • Lord BI, Woolford LB, Molineux G (2001) Kinetics of neutrophil production in normal and neutropenic animals during the response to filgrastim (r-metHu G-CSF) or filgrastim SD/01 (PEG-r-metHu G-CSF). Clin Cancer Res 7:2085–2090

    CAS  PubMed  Google Scholar 

  • McEver RP (2001) Adhesive interactions of leukocytes, platelets, and the vessel wall during hemostasis and inflammation. Thromb Haemost 86:746–756

    CAS  PubMed  Google Scholar 

  • Micallef IN, Stiff PJ, DiPersio JF, Maziarz RT, McCarty JM, Bridger G, Calandra G (2009) Succesful stem cell remobilization using Plerixafor (Mozobil) plus granulocyte colony-stimulating factor in patients with non-Hodgkin lymphoma: results from the Plerixafor NHL phase 3 study rescue protocol. Biol Blood Marrow Transplant 15:1578–1586

    Article  CAS  PubMed  Google Scholar 

  • Miner JJ, Xia L, Yago T, Kappelmayer J, Liu Z, Klopocki AG, Shao B, McDaniel JM, Setiadi H, Schmidtke DW, McEver RP (2008) Separable requirements for cytoplasmic domain of PSGL-1 in leukocyte rolling and signaling under flow. Blood 112:2035–2045

    Article  CAS  PubMed  Google Scholar 

  • Miszti-Blasius K, Debreceni IB, Felszeghy S, Dezso B, Kappelmayer J (2011) Lack of P-selectin glycoprotein ligand-1 protects mice from thrombosis after collagen/epinephrine challenge. Thromb Res 127:228–234

    Article  CAS  PubMed  Google Scholar 

  • Nagy B Jr, Miszti-Blasius K, Kerenyi A, Clemetson KJ, Kappelmayer J (2012) Potential therapeutic targeting of platelet-mediated cellular interactions in atherosclerosis and inflammation. Curr Med Chem 19:518–531

    Article  CAS  PubMed  Google Scholar 

  • Nemeth N, Kiss F, Furka I, Miko I (2010) Gender differences of blood rheological parameters in laboratory animals. Clin Hemorheol Microcirc 45:263–272

    PubMed  Google Scholar 

  • Nervi B, Lin DC, DiPersio JF (2006) Cytokines and ematopoietic stem cell mobilization. J Cell Biochem 99:690–705

    Article  CAS  PubMed  Google Scholar 

  • Paganessi LA, Walker AL, Tan LL, Holmes I, Rich E, Fung HC, Christopherson KW 2nd (2011) Effective mobilization of hematopoietic progenitor cells in G-CSF mobilization defective CD26−/− mice through AMD3100-induced disruption of the CXCL12-CXCR4 axis. Exp Hematol 39:384–390

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Palicz Z, Jenes A, Gáll T, Miszti-Blasius K, Kollár S, Kovács I, Emri M, Márián T, Leiter E, Pócsi I, Csősz E, Kalló G, Hegedűs C, Virág L, Csernoch L, Szentesi P (2013) In vivo application of a small molecular weight antifungal protein of Penicillium chrysogenum (PAF). Toxicol Appl Pharmacol 269:8–16

    Article  CAS  PubMed  Google Scholar 

  • Patel KD, McEver RP (1997) Comparison of tethering and rolling of eosinophils and neutrophils through selectins and P-selectin glycoprotein ligand-1. J Immun 159:4555–4565

    CAS  PubMed  Google Scholar 

  • Pelus LM (2008) Peripheral blood stem cell mobilization: new regimens, new cells, where do we stand. Curr Opin Hematol 15:285–292

    Article  PubMed Central  PubMed  Google Scholar 

  • Richman CM, Weiner RS, Yankee RA (1976) Increase in circulating stem cells following chemotherapy in man. Blood 47:1031–1039

    CAS  PubMed  Google Scholar 

  • Sato T, Laver JH, Ogawa M (1999) Reversible expression of CD34 by murine hematopoietic stem cells. Blood 94:2548–2554

    CAS  PubMed  Google Scholar 

  • Sperandio M, Smith ML, Forlow SB, Olson TS, Xia L, McEver RP, Ley K (2003) P-selectin Glycoprotein Ligand-1 mediates L-selectin-dependent leukocyte rolling in venules. J Exp Med 197:1355–1363

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Ushiyama S, Lau TM, Moore KL, Erickson HP, McEver RP (1993) Structural and functional characterization of monomeric soluble P-selectin and comparison with membrane P-selectin. J Biol Chem 268:15229–15237

    CAS  PubMed  Google Scholar 

  • Xia L, Sperandio M, Yago T, McDaniel JM, Cummings RD, Pearson-White S, Ley K, McEver RP (2002) P-selectin glycoprotein ligand-1-deficient mice have impaired leukocyte tethering to E-selectin under flow. J Clin Invest 109:939–950

    CAS  PubMed Central  PubMed  Google Scholar 

  • Wojciechowski JC, Narasipura SD, Charles N, Mickelsen D, Rana K, Blair ML, King MR (2008) Capture and enrichment of CD34-positive haematopoietic stem and progenitor cells from blood circulation using P-selectin in an implantable device. Br J Haematol 140:673–681

    Article  PubMed Central  PubMed  Google Scholar 

  • Zarbock A, Ley K, McEver RP, Hidalgo A (2011) Leukocyte ligands for endothelial selectins: specialized glycoconjugates that mediate rolling and signaling under flow. Blood 118:6743–6751

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The authors acknowledge Dr. Rodger McEver and Lijun Xia (Oklahoma Medical Research Foundation, Oklahoma City, OK, USA) for providing the PSGL-1 knockout mice. The excellent assistance of Marianna Dobrai, Katalin Orosz-Tóth, Tünde Terdik Pál and Tamás Papp are acknowledged. This research was supported by the European Union and the State of Hungary, co-financed by the European Social Fund in the framework of TÁMOP 4.2.4. A/2-11-1-2012-0001 ‘National Excellence Program’. (K. M-B). Immunohistological analysis was conducted by the Korean Research Fund of the University of Debrecen (Sz. F.).

Conflict of interest

The authors declare no conflict of interest.

Author information

Authors and Affiliations

  1. Department of Laboratory Medicine, Medical and Health Science Center, University of Debrecen, Nagyerdei krt 98, 4032, Debrecen, Hungary

    Kornél Miszti-Blasius, Zsuzsanna Hevessy & János Kappelmayer

  2. Department of Anatomy Histology and Embriology, Medical and Health Science Center, University of Debrecen, Debrecen, Hungary

    Szabolcs Felszeghy

  3. Department of Pediatric Hematology, Medical and Health Science Center, University of Debrecen, Debrecen, Hungary

    Csongor Kiss

  4. Department of Pharmacology and Pharmacotherapy, Medical and Health Science Center, University of Debrecen, Debrecen, Hungary

    Ilona Benkő, Krisztina Géresi & Attila Megyeri

Authors
  1. Kornél Miszti-Blasius
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Szabolcs Felszeghy
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Csongor Kiss
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ilona Benkő
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Krisztina Géresi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Attila Megyeri
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Zsuzsanna Hevessy
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. János Kappelmayer
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to János Kappelmayer.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Miszti-Blasius, K., Felszeghy, S., Kiss, C. et al. P-selectin glycoprotein ligand-1 deficiency augments G-CSF induced myeloid cell mobilization. Naunyn-Schmiedeberg's Arch Pharmacol 387, 109–118 (2014). https://doi.org/10.1007/s00210-013-0913-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00210-013-0913-9

Keywords

Search

Navigation