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W. Wojakowski, MD, FESC Silesian School of Medicine, Katowice, Poland

Pleiotropic effects of cytokines on left ventricular remodelling and cardiovascular stem cell therapy. W. Wojakowski, MD, FESC Silesian School of Medicine, Katowice, Poland. Financial disclousure:

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W. Wojakowski, MD, FESC Silesian School of Medicine, Katowice, Poland

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  1. Pleiotropic effects of cytokineson left ventricular remodelling and cardiovascular stem cell therapy W. Wojakowski, MD, FESC Silesian School of Medicine, Katowice, Poland

  2. Financial disclousure: Supported by the grants from Polish Ministry of Science and Higher Education, Servier Research Grant and European Vascular Genomics Network (EVGN) No conflict of interest

  3. MOBILIZATION OF BONE MARROW-DERIVED • CARDIOGENIC DIFFERENTIATION OF BM- DERIVED CELLS, • DIRECT EFFECTS ON CARDIOMYOCYTES, • MARKERS OF MYOCARDIAL INJURY, • NON-SPECIFIC MARKERS OF TISSUE INJURY HEMATOPOIETIC AND INFLAMMATORY CYTOKINES

  4. * p<0.0001 vs. CTRL ** p<0.003 vs. CTRL *** p=ns vs. CTRL * * ** ** * * p<0.05 vs. baseline ** p<0.0001 vs. baseline *** p=ns vs. baseline *** *** Wojakowski, Circulation 2004;110:3213 Massa, Blood 2005,105:199 Mieno, Circulation 2006;114:186

  5. control PBMNC 24h after infarct PBMNC 48h after infarct PBMNC 7 days after infarct 40 30 20 fold of difference 10 0 Myf5 MyoD MEF2C GATA-4 Myogenin Nkx2.5/Csx VE-cadherin Von Willenbrand cardiac markers muscle markers endothelial markers Wojakowski, Circulation 2004;110:3213

  6. p<0.01 p<0.03 p<0.03 CD34/CXCR4+ [cells/µL] SDF-1[pg/mL]

  7. Correlation between CD34+ cells and LV function at 1 year follow-up Leoneet al. Eur Heart J 2005; 26

  8. 1-YEAR FOLLOW-UP BY cMRI Baseline CD34/CXCR4+cells: • negatively correlated with LV remodeling: LVEDV (r=-0.31; p<0.03), LVESV (r=-0.34; p<0.04). Baseline CD34/CXCR4+ cells: • negatively correlated with the mean delayed enhancement after 1 year (r=-0.30; p<0.03) • number of segments displaying impaired stress first pass perfusion (r=-0.57; p<0.05) Wojakowski, AHA 2006

  9. 1-YEAR FOLLOW-UP (cMRI) ACUTE FOLLOW-UP CD34/CXCR4+; R=0.51, p=0.002 CD34/CXCR4+; R=0.48, p=0.004 Baseline and 12 month SDF-1 levels: • no correlations with LVEF, LV remodeling, • myocardial perfusion • no correlation with cardiopulmonary exercise test Wojakowski, AHA 2006

  10. SDF-1 IN PERIINFARCT MYOCYTES AND VESSELS REMOTE MYOCARDIUM Abbott, Circulation 2004,110:3300 Kucia, M. et al. Circ Res 2004;95:1191

  11. BMMNCchemoattracted to the infarcted myocardium in SDF-1-, HGF- and LIF-dependent manner Kucia, Circ Res 2004;95:1190

  12. Kucia, Circ Res 2004;95:1191

  13. CXCR4 C-Met LIF-R Bone Marrow Skeletal Muscle Other Tissues Peripheral Blood Myocardium Brain SDF-1 HGF LIF gradient Very Small TCSC Number Low Expression of Cardiac/Endothelial Markers Ratajczak, Biol Cell 2005, 97, 113-146. Wojakowski, Heart 2007

  14. CXCR4 c-Met LIF-R Infarcted Myocardium Bone Marrow Skeletal Muscle Other Tissues Peripheral Blood SDF-1 HGF LIF gradient Increased Number Increased Expression of Cardiac/Endothelial Markers Mobilization Homing/Engraftment Ratajczak, Biol Cell 2005, 97, 113-146. Wojakowski, Heart 2007

  15. REGENT TRIAL NCT 00316381 STEMI + LVEF≤40% (PRIMARY PCI <12 hrs.) randomization MRI, LV-ANGIO, ECHO, CONTRAST ECHO, CARDIOPULMONARY EXERCISE TEST CONTROL BMCells TREATMENT BONE MARROW ASPIRATE (100-120 mL) NON-SELECTED BM MNC CD34/CXCR4+ CELLS IMMUNOMAGNETIC SELECTION 6 MO. MRI, LV-ANGIO, ECHO, CONTRAST ECHO, CARDIOPULMONARY EXERCISE TEST 12 MO. ECHO, CLINICAL F-U

  16. IT SEEMS THAT SDF-1 ATTRACTS LOTS OF INTERESTING THINGS… CXCR4

  17. Bone Marrow Mononuclear Cells Chemotaxis to SDF-1 Medium alone SDF-1 FACS SORTER CD45-CD45+ CXCR4+CD45- CXCR4+CD45+

  18. Which cells are attracted by SDF-1 ? Biol Cell 2005, 97, 113-146

  19. SSC Lineage PE 0.16% 50.5% Sca-1 PE-Cy5 FSC 0.009% 0.15% Counts Sca-1+lin-CD45- Sca-1+lin-CD45+ CD45 APC-Cy7

  20. Very Small Embryonic Like (VSEL) Stem Cell Hematopoietic Stem Cell Sca-1+lin-CD45+ Sca-1+lin-CD45- Leukemia 2006,20:857-869

  21. RQ-PCR analysis inSca-1+lin-CD45- cells Leukemia 2006,20:857-869

  22. unpurified BMMNC Sca-1+lin-CD45+ Sca-1+lin-CD45- AP staining on ES-D3 cell-derived embryonic bodies AP staining on VSEL derived embryonic like bodies SSEA-1 Oct4 Nanog Leukemia 2006,20:857-869

  23. b myosin heavy chain troponin I Kucia, Circ Res 2004;95:1190 Leukemia 2006, 20, 18- 28

  24. Transcriptional profile of VSEL-derived cardiomyocytes • Genes with higher expressionin VSELs vs. differentiation series: • CXCR4, • TGFβ SIGNALLING • Genes down-regulated in VSELs • vs. differentiation series: • ION CHANNELS (K+, Ca2+), CONNEXINS • LIFR, c-kit, c-met • CELL MOTILITY, • FIBRONECTIN RECEPTOR COMPLEX, • CARDIAC AND VESSEL DEVELOPMENT Wojakowski, ACC 2007

  25. * vs. control # vs. sham control P < 0.05 A B # * # * # * # * Control Control Sham control Sham control 24h 24h 48h 7 days 48h 7 days Mobilization of HSC and VSEL into peripheral blood after AMI Courtesy of MZ Ratajczak

  26. CONTROL 0,12 0,08 0,05 STEMI 0,32 0,21 0,06 Massa, Blood 2005,105:199 Wojakowski, Circulation 2004;110:3213

  27. Fazel, J. Clin. Invest. 2006;116:1865

  28. SDF-1 / CXCR4 • HGF / c-met • SCF / c-kit • LIF / LIFR • VEGF / VEGFR • G-CSF / G-CSFR • GM-CSF / GM-CSFR • M-CSF / M-CSFR • flt3 – FL • Epo - EpoR

  29. G-CSF induced mobilization • G-CSF and HSC: • proliferation, • differentiation, • survival • G-CSF and non-HSC: cardiomyocytes, • endothelial cells, • neuronal cells G-CSF

  30. REVIVAL-2 STEMMI MRI GCSF vs. placebo, p=NS Regional systolic wall thickening GCSF vs. placebo, p=NS Zohlnhofer et al.: JAMA 2006,295,1003 Ripa et al.: Circulation 2006,113

  31. Migratory capacity of transplanted progenitor cells and infarct remodeling Britten, Circulation 2003;108:2212

  32. Migratory activity of nonmobilized and G-CSF-mobilized EPC Honold, ATVB 2006;26:2238-2243

  33. IMPROVED CONTRACTILITY IN AREAS REMOTE FROM THE INFARCT AREA • MYOCARDIAL REGENERATION AND PROLIFERATION CONFINED TO INFARCTED AREA • RESPONSIVENESS OF BONE MARROW CELLS TO CHEMOATTRACTANTS DECLINES IN AGE-DEPENDENT FASHION • STANDAD MOBILIZATION AGENTS (G-CSF) IMPAIR THE RESPONSIVENES OF PROGENITOR CELLS TO PIVOTAL CHEMOATTRACTANTS CELL MOBILIZATION FOR IMPROVEMENT OF LV FUNCTION

  34. Combination of cytokines in murine model of reperfused MI G-CSF G-CSF + FL (flt3 ligand) G-CSF+SCF Dawn, B. et al. Circ Res 2006;98:1098

  35. lin-/Sca-1+/c-kit+ cells from untreated bone marrow and peripheral blood Dawn, B. et al. Circ Res 2006;98:1098

  36. COMBINATION OF CYTOKINES • improved mobilization • qualitative differences in function of mobilized cells (adhesion molecules) • higher rate of cardiomyocyte proliferation • better LV lunction, reduced remodeling

  37. A B C UPREGULATION OF SDF-1 SDF-1 Leukemia 2004, 18: 29-40 D Aicher, Circulation 2006;114:2823

  38. HEMATOPOIETIC CYTOKINES • MOBILIZATION OF BM-DERIVED PROGENITORS - INCREASED EXTRAVASATION, HOMING - INCREASED EXPRSSION OF ADHESION MOLECULES • TRANSDIFFERENTIATION INTO CARDIOMYOCYTES(?) • MIGRATION AND PROLIFERATION OF RESIDENT CARDIAC STEM CELLS • PARACRINE EFFECTS OF THE RECRUITED CELLS - ANTIAPOPTOTIC EFFECT - FAVOURABLE CHANGES IN ECM - INCREASED ANGIOGENESIS

  39. KRAKÓW Marcin Majka Ania Zebzda LOUISVILLE Mariusz Z. Ratajczak Magdalena Kucia Janina Ratajczak Ewa Zuba-Surma Ryan Reca KATOWICE Michał Tendera Paweł Buszman Marek Król Kasia Maślankiewicz Andrzej Pyrlik Radek Parma Rafał Wyderka Joanna Ciosek Sebastian Dworowy Iwona Mróz BRISTOL Paolo Madeddu Nicole Kraenkel Constanza Emanueli SZCZECIN Bogdan Machaliński, Maciek Halasa

  40. GOOD THING ABOUT BEING INTERVENTIONAL CARDIOLOGIST IS TO GET A LOT OF EXPERIENCE IN HEMATOLOGY THANK YOU

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