Skip to main content
SpringerLink
Log in

Enhanced stem cell migration mediated by VCAM-1/VLA-4 interaction improves cardiac function in virus-induced dilated cardiomyopathy

  • Original Contribution
  • Published:
Basic Research in Cardiology Aims and scope Submit manuscript

Abstract

Endogenous circulation of bone marrow-derived cells (BMCs) was observed in patients with dilated cardiomyopathy (DCM) who showed cardiac upregulation of Vascular Cell Adhesion Protein-1 (VCAM-1). However, the underlying pathophysiology is currently unknown. Thus, we aimed to analyze circulation, migration and G-CSF-based mobilization of BMCs in a murine model of virus-induced DCM. Mice with coxsackievirus B3 (CVB3) induced DCM and healthy controls were analyzed regarding their myocardial homing factors by PCR. To determine cardiac VCAM-1 expression ELISA and immunohistochemistry were applied. Flow cytometry was performed to analyze BMCs. Cardiac diameters and function were evaluated by echocardiography before and 4 weeks after G-CSF treatment. In murine CVB3-induced DCM an increase of BMCs in peripheral blood and a decrease of BMCs in bone marrow was observed. We found an enhanced migration of Very Late Antigen-4 (VLA-4+) BMCs to the diseased heart overexpressing VCAM-1 and higher numbers of CD45−CD34−Sca-1+ and CD45−CD34−c-kit+ cells. Mobilization of BMCs by G-CSF boosted migration along the VCAM-1/VLA-4 axis and reduced apoptosis of cardiomyocytes. Significant improvement of cardiac function was detected by echocardiography in G-CSF-treated mice. Blocking VCAM-1 by a neutralizing antibody reduced the G-CSF-dependent effects on stem cell migration and cardiac function. This is the first study showing that in virus-induced DCM VCAM-1/VLA-4 interaction is crucial for recruitment of circulating BMCs leading to beneficial anti-apoptotic effects resulting in improved cardiac function after G-CSF-induced mobilization.

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
Fig. 8

Similar content being viewed by others

References

  1. Aicher A, Heeschen C, Mildner-Rihm C, Urbich C, Ihling C, Technau-Ihling K, Zeiher AM, Dimmeler S (2003) Essential role of endothelial nitric oxide synthase for mobilization of stem and progenitor cells. Nat Med 9:1370–1376. doi:10.1038/nm948

    Article  PubMed  CAS  Google Scholar 

  2. Askari AT, Unzek S, Popovic ZB, Goldman CK, Forudi F, Kiedrowski M, Rovner A, Ellis SG, Thomas JD, DiCorleto PE, Topol EJ, Penn MS (2003) Effect of stromal-cell-derived factor 1 on stem-cell homing and tissue regeneration in ischaemic cardiomyopathy. Lancet 362:697–703. doi:10.1016/S0140-6736(03)14232-8

    Article  PubMed  CAS  Google Scholar 

  3. Brunner S, Engelmann MG, Franz WM (2008) Stem cell mobilisation for myocardial repair. Expert Opin Biol Ther 8:1675–1690. doi:10.1016/S0140-6736(03)14232-8

    Article  PubMed  CAS  Google Scholar 

  4. Brunner S, Huber BC, Fischer R, Groebner M, Hacker M, David R, Zaruba MM, Vallaster M, Rischpler C, Wilke A, Gerbitz A, Franz WM (2008) G-CSF treatment after myocardial infarction: impact on bone marrow-derived vs cardiac progenitor cells. Exp Hematol 36(6):695–702. doi:10.1016/j.exphem.2008.01.011

    Article  PubMed  CAS  Google Scholar 

  5. Buccini S, Haider KH, Ahmed RP, Jiang S, Ashraf M (2012) Cardiac progenitors derived from reprogrammed mesenchymal stem cells contribute to angiomyogenic repair of the infarcted heart. Basic Res Cardiol 107:301. doi:10.1007/s00395-012-0301-5

    Article  PubMed  Google Scholar 

  6. Cooper LT Jr (2009) Myocarditis. N Engl J Med 360:1526–1538. doi:10.1056/NEJMra0800028

    Article  PubMed  CAS  Google Scholar 

  7. Deindl E, Zaruba MM, Brunner S, Huber B, Mehl U, Assmann G, Hoefer IE, Mueller-Hoecker J, Franz WM (2006) G-CSF administration after myocardial infarction in mice attenuates late ischemic cardiomyopathy by enhanced arteriogenesis. Faseb J 20:956–958. doi:10.1096/fj.05-4763fje

    Article  PubMed  CAS  Google Scholar 

  8. Devaux B, Scholz D, Hirche A, Klovekorn WP, Schaper J (1997) Upregulation of cell adhesion molecules and the presence of low grade inflammation in human chronic heart failure. Eur Heart J 18:470–479. doi:0195-668X/97/030470

    Article  PubMed  CAS  Google Scholar 

  9. Fadini GP, Albiero M, Seeger F, Poncina N, Menegazzo L, Angelini A, Castellani C, Thiene G, Agostini C, Cappellari R, Boscaro E, Zeiher A, Dimmeler S, Avogaro A (2013) Stem cell compartmentalization in diabetes and high cardiovascular risk reveals the role of DPP-4 in diabetic stem cell mobilopathy. Basic Res Cardiol 108:313. doi:10.1007/s00395-012-0313-1

    Article  PubMed  Google Scholar 

  10. Harada M, Qin Y, Takano H, Minamino T, Zou Y, Toko H, Ohtsuka M, Matsuura K, Sano M, Nishi J, Iwanaga K, Akazawa H, Kunieda T, Zhu W, Hasegawa H, Kunisada K, Nagai T, Nakaya H, Yamauchi-Takihara K, Komuro I (2005) G-CSF prevents cardiac remodeling after myocardial infarction by activating the Jak-Stat pathway in cardiomyocytes. Nat Med 11:305–311. doi:10.1038/nm1199

    Article  PubMed  CAS  Google Scholar 

  11. Hiraoka Y, Kishimoto C, Takada H, Suzaki N, Shiraki K (1995) Effects of granulocyte colony-stimulating factor upon coxsackievirus B3 myocarditis in mice. Eur Heart J 16:1900–1906

    PubMed  CAS  Google Scholar 

  12. Huber SA (1994) VCAM-1 is a receptor for encephalomyocarditis virus on murine vascular endothelial cells. J Virol 68:3453–3458

    PubMed  CAS  Google Scholar 

  13. Jansen J, Hanks S, Thompson JM, Dugan MJ, Akard LP (2005) Transplantation of hematopoietic stem cells from the peripheral blood. J Cell Mol Med 9:37–50. doi:10.1111/j.1582-4934.2005.tb00335.x

    Article  PubMed  Google Scholar 

  14. Jin H, Aiyer A, Su J, Borgstrom P, Stupack D, Friedlander M, Varner J (2006) A homing mechanism for bone marrow-derived progenitor cell recruitment to the neovasculature. J Clin Invest 116:652–662. doi:10.1172/JCI24751

    Article  PubMed  CAS  Google Scholar 

  15. Kandolf R, Hofschneider PH (1985) Molecular cloning of the genome of a cardiotropic Coxsackie B3 virus: full-length reverse-transcribed recombinant cDNA generates infectious virus in mammalian cells. Proc Natl Acad Sci USA 82:4818–4822

    Article  PubMed  CAS  Google Scholar 

  16. Klingel K, Hohenadl C, Canu A, Albrecht M, Seemann M, Mall G, Kandolf R (1992) Ongoing enterovirus-induced myocarditis is associated with persistent heart muscle infection: quantitative analysis of virus replication, tissue damage, and inflammation. Proc Natl Acad Sci USA 89:314–318

    Article  PubMed  CAS  Google Scholar 

  17. Klingel K, Sauter M, Bock CT, Szalay G, Schnorr JJ, Kandolf R (2004) Molecular pathology of inflammatory cardiomyopathy. Med Microbiol Immunol 193:101–107. doi:10.1007/s00430-003-0190-1

    Article  PubMed  CAS  Google Scholar 

  18. Koch AE, Halloran MM, Haskell CJ, Shah MR, Polverini PJ (1995) Angiogenesis mediated by soluble forms of E-selectin and vascular cell adhesion molecule-1. Nature 376:517–519. doi:10.1038/376517a0

    Article  PubMed  CAS  Google Scholar 

  19. Kocher AA, Schuster MD, Szabolcs MJ, Takuma S, Burkhoff D, Wang J, Homma S, Edwards NM, Itescu S (2001) Neovascularization of ischemic myocardium by human bone-marrow-derived angioblasts prevents cardiomyocyte apoptosis, reduces remodeling and improves cardiac function. Nat Med 7:430–436. doi:10.1038/86498

    Article  PubMed  CAS  Google Scholar 

  20. Kwee L, Baldwin HS, Shen HM, Stewart CL, Buck C, Buck CA, Labow MA (1995) Defective development of the embryonic and extraembryonic circulatory systems in vascular cell adhesion molecule (VCAM-1) deficient mice. Development 121:489–503

    PubMed  CAS  Google Scholar 

  21. Lang C, Sauter M, Szalay G, Racchi G, Grassi G, Rainaldi G, Mercatanti A, Lang F, Kandolf R, Klingel K (2008) Connective tissue growth factor: a crucial cytokine-mediating cardiac fibrosis in ongoing enterovirus myocarditis. J Mol Med 86:49–60. doi:10.1007/s00109-007-0249-3

    Article  PubMed  CAS  Google Scholar 

  22. Lorenzen JM, Martino F, Thum T (2012) Epigenetic modifications in cardiovascular disease. Basic Res Cardiol 107:245. doi:10.1007/s00395-012-0245-9

    Article  PubMed  Google Scholar 

  23. Maron BJ, Doerer JJ, Haas TS, Tierney DM, Mueller FO (2009) Sudden deaths in young competitive athletes: analysis of 1866 deaths in the United States, 1980–2006. Circulation 119:1085–1092. doi:10.1161/CIRCULATIONAHA.108.804617

    Article  PubMed  Google Scholar 

  24. Mason JW (2003) Myocarditis and dilated cardiomyopathy: an inflammatory link. Cardiovasc Res 60:5–10. doi:10.1016/S0008-6363(03)00437-1

    Article  PubMed  CAS  Google Scholar 

  25. Matsuura K, Honda A, Nagai T, Fukushima N, Iwanaga K, Tokunaga M, Shimizu T, Okano T, Kasanuki H, Hagiwara N, Komuro I (2009) Transplantation of cardiac progenitor cells ameliorates cardiac dysfunction after myocardial infarction in mice. J Clin Invest 119:2204–2217. doi:10.1172/JCI37456

    PubMed  CAS  Google Scholar 

  26. Orlic D, Kajstura J, Chimenti S, Limana F, Jakoniuk I, Quaini F, Nadal-Ginard B, Bodine DM, Leri A, Anversa P (2001) Mobilized bone marrow cells repair the infarcted heart, improving function and survival. Proc Natl Acad Sci USA 98:10344–10349. doi:10.1073/pnas.181177898

    Article  PubMed  CAS  Google Scholar 

  27. Rudolph V, Andrie RP, Rudolph TK, Friedrichs K, Klinke A, Hirsch-Hoffmann B, Schwoerer AP, Lau D, Fu X, Klingel K, Sydow K, Didie M, Seniuk A, von Leitner EC, Szoecs K, Schrickel JW, Treede H, Wenzel U, Lewalter T, Nickenig G, Zimmermann WH, Meinertz T, Boger RH, Reichenspurner H, Freeman BA, Eschenhagen T, Ehmke H, Hazen SL, Willems S, Baldus S (2010) Myeloperoxidase acts as a profibrotic mediator of atrial fibrillation. Nat Med 16:470–474. doi:10.1038/nm.2124

    Article  PubMed  CAS  Google Scholar 

  28. Rutschow S, Leschka S, Westermann D, Puhl K, Weitz A, Ladyszenskij L, Jaeger S, Zeichhardt H, Noutsias M, Schultheiss HP, Tschope C, Pauschinger M (2010) Left ventricular enlargement in coxsackievirus-B3 induced chronic myocarditis-ongoing inflammation and an imbalance of the matrix degrading system. Eur J Pharmacol 630:145–151. doi:10.1016/j.ejphar.2009.12.019

    Article  PubMed  CAS  Google Scholar 

  29. Sanganalmath SK, Abdel-Latif A, Bolli R, Xuan YT, Dawn B (2011) Hematopoietic cytokines for cardiac repair: mobilization of bone marrow cells and beyond. Basic Res Cardiol 106:709–733. doi:10.1007/s00395-011-0183-y

    Article  PubMed  CAS  Google Scholar 

  30. Seko Y, Yagita H, Okumura K, Yazaki Y (1996) Expression of vascular cell adhesion molecule-1 in murine hearts with acute myocarditis caused by coxsackievirus B3. J Pathol 180:450–454. doi:10.1002/(SICI)1096-9896(199612)180:4<450:AID-PATH693>3.0.CO;2-5

    Article  PubMed  CAS  Google Scholar 

  31. Shimada K, Okabe TA, Mikami Y, Hattori M, Fujita M, Kishimoto C (2010) Therapy with granulocyte colony-stimulating factor in the chronic stage, but not in the acute stage, improves experimental autoimmune myocarditis in rats via nitric oxide. J Mol Cell Cardiol 49(3):469–481. doi:10.1016/j.yjmcc.2010.02.003

    Article  PubMed  CAS  Google Scholar 

  32. Stevens PJ, Ground KE (1970) Occurrence and significance of myocarditis in trauma. Aerosp Med 41:776–780

    PubMed  CAS  Google Scholar 

  33. Szalay G, Sauter M, Hald J, Weinzierl A, Kandolf R, Klingel K (2006) Sustained nitric oxide synthesis contributes to immunopathology in ongoing myocarditis attributable to interleukin-10 disorders. Am J Pathol 169:2085–2093. doi:10.2353/ajpath.2006.060350

    Article  PubMed  CAS  Google Scholar 

  34. Theiss HD, Brenner C, Engelmann MG, Zaruba MM, Huber B, Henschel V, Mansmann U, Wintersperger B, Reiser M, Steinbeck G, Franz WM (2010) Safety and efficacy of SITAgliptin plus GRanulocyte-colony-stimulating factor in patients suffering from Acute Myocardial Infarction (SITAGRAMI-Trial)—Rationale, design and first interim analysis. Int J Cardiol 145(2):282–284. doi:10.1016/j.ijcard.2009.09.555

    Article  PubMed  Google Scholar 

  35. Theiss HD, David R, Engelmann MG, Barth A, Schotten K, Naebauer M, Reichart B, Steinbeck G, Franz WM (2007) Circulation of CD34+ progenitor cell populations in patients with idiopathic dilated and ischaemic cardiomyopathy (DCM and ICM). Eur Heart J 28:1258–1264. doi:10.1093/eurheartj/ehm011

    Article  PubMed  Google Scholar 

  36. Theiss HD, Vallaster M, Rischpler C, Krieg L, Zaruba MM, Brunner S, Vanchev Y, Fischer R, Grobner M, Huber B, Wollenweber T, Assmann G, Mueller-Hoecker J, Hacker M, Franz WM (2011) Dual stem cell therapy after myocardial infarction acts specifically by enhanced homing via the SDF-1/CXCR4 axis. Stem Cell Res 7(3):244–255. doi:10.1016/j.scr.2011.05.003

    Article  PubMed  CAS  Google Scholar 

  37. Wu J, Li J, Zhang N, Zhang C (2011) Stem cell-based therapies in ischemic heart diseases: a focus on aspects of microcirculation and inflammation. Basic Res Cardiol 106:317–324. doi:10.1007/s00395-011-0168-x

    Article  PubMed  Google Scholar 

  38. Yang JT, Rayburn H, Hynes RO (1995) Cell adhesion events mediated by alpha 4 integrins are essential in placental and cardiac development. Development 121:549–560

    PubMed  CAS  Google Scholar 

  39. Yilmaz A, Kindermann I, Kindermann M, Mahfoud F, Ukena C, Athanasiadis A, Hill S, Mahrholdt H, Voehringer M, Schieber M, Klingel K, Kandolf R, Bohm M, Sechtem U (2010) Comparative evaluation of left and right ventricular endomyocardial biopsy: differences in complication rate and diagnostic performance. Circulation 122(9):900–909. doi:10.1161/CIRCULATIONAHA.109.924167

    Article  PubMed  Google Scholar 

  40. Zaruba MM, Franz WM (2010) Role of the SDF-1-CXCR4 axis in stem cell-based therapies for ischemic cardiomyopathy. Expert Opin Biol Ther 10:321–335. doi:10.1517/14712590903460286

    Article  PubMed  CAS  Google Scholar 

  41. Zaruba MM, Theiss HD, Vallaster M, Mehl U, Brunner S, David R, Fischer R, Krieg L, Hirsch E, Huber B, Nathan P, Israel L, Imhof A, Herbach N, Assmann G, Wanke R, Mueller-Hoecker J, Steinbeck G, Franz WM (2009) Synergy between CD26/DPP-IV inhibition and G-CSF improves cardiac function after acute myocardial infarction. Cell Stem Cell 4:313–323. doi:10.1016/j.stem.2009.02.013

    Article  CAS  Google Scholar 

  42. Zohlnhofer D, Dibra A, Koppara T, de Waha A, Ripa RS, Kastrup J, Valgimigli M, Schomig A, Kastrati A (2008) Stem cell mobilization by granulocyte colony-stimulating factor for myocardial recovery after acute myocardial infarction: a meta-analysis. J Am Coll Cardiol 51:1429–1437. doi:10.1016/j.jacc.2007.11.073

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

We want to thank Judith Arcifa, Barbara Markieton and Sandra Bundschuh for excellent technical assistance. The position of Barbara Markieton was funded by the Fritz-Bender-Stiftung. The position of Markus Vallaster was funded by the FöFoLe program of the LMU Munich. Additional financial support was provided by the DFG, by the FöFoLe program of the LMU Munich, by the Dr. Helmut Legerlotz-Stiftung, and by the Else Kröner-Fresenius-Stiftung. Karin Klingel and Reinhard Kandolf received financial support by the DFG (SFB-TR19) and the BMBF 01EZ0817.

Conflict of interest

On behalf of all authors, the corresponding authors state that there is no conflict of interest.

Author information

Authors and Affiliations

  1. Medical Department I, Klinikum Grosshadern, Ludwig-Maximilians-University, Marchioninistr. 15, 81377, Munich, Germany

    Stefan Brunner, Hans D. Theiss, Monika Leiss, Ulrich Grabmaier, Johanna Grabmeier, Bruno Huber, Markus Vallaster & Wolfgang-Michael Franz

  2. Department of Radiology, Klinikum Grosshadern, Ludwig-Maximilians-University, Munich, Germany

    Dirk Andre Clevert

  3. Department of Molecular Pathology, University Hospital of Tuebingen, Tübingen, Germany

    Martina Sauter, Reinhard Kandolf & Karin Klingel

  4. Reference and Translation Center for Cardiac Stem Cell Therapy (RTC), University of Rostock, Rostock, Germany

    Christian Rimmbach & Robert David

Authors
  1. Stefan Brunner
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hans D. Theiss
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Monika Leiss
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ulrich Grabmaier
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Johanna Grabmeier
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Bruno Huber
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Markus Vallaster
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Dirk Andre Clevert
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Martina Sauter
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Reinhard Kandolf
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Christian Rimmbach
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Robert David
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Karin Klingel
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Wolfgang-Michael Franz
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Stefan Brunner or Wolfgang-Michael Franz.

Additional information

S. Brunner and H. D. Theiss contributed equally to this work.

K. Klingel and W.-M. Franz share senior authorship.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Brunner, S., Theiss, H.D., Leiss, M. et al. Enhanced stem cell migration mediated by VCAM-1/VLA-4 interaction improves cardiac function in virus-induced dilated cardiomyopathy. Basic Res Cardiol 108, 388 (2013). https://doi.org/10.1007/s00395-013-0388-3

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s00395-013-0388-3

Keywords

Search

Navigation