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Pleiotropic effects of cytokines on left ventricular remodelling and cardiovascular stem cell therapy

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Pleiotropic effects of cytokines on left ventricular remodelling and cardiovascular stem cell therapy W. Wojakowski, MD, FESC Silesian School of Medicine ... – PowerPoint PPT presentation

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Title: Pleiotropic effects of cytokines on left ventricular remodelling and cardiovascular stem cell therapy


1
Pleiotropic effects of cytokines on
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
HEMATOPOIETIC AND INFLAMMATORY CYTOKINES
  • 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

4
plt0.0001 vs. CTRL plt0.003 vs. CTRL pns
vs. CTRL





plt0.05 vs. baseline plt0.0001 vs.
baseline pns vs. baseline


Wojakowski, Circulation 20041103213 Massa,
Blood 2005,105199 Mieno, Circulation 2006114186
5
Wojakowski, Circulation 20041103213
6
plt0.01
plt0.03
plt0.03
CD34/CXCR4 cells/µL
SDF-1 pg/mL
7
Correlation between CD34 cells and LV function
at 1 year follow-up
Leone et 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 plt0.03), LVESV (r-0.34
    plt0.04).
  • Baseline CD34/CXCR4 cells
  • negatively correlated with the mean delayed
    enhancement after 1 year
    (r-0.30 plt0.03)
  • number of segments displaying impaired stress
    first pass perfusion (r-0.57 plt0.05)

Wojakowski, AHA 2006
9
1-YEAR FOLLOW-UP (cMRI)
ACUTE
FOLLOW-UP
CD34/CXCR4 R0.51, p0.002
CD34/CXCR4 R0.48, p0.004
  • 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
Abbott, Circulation 2004,1103300 Kucia, M. et
al. Circ Res 2004951191
11
BMMNC chemoattracted to the infarcted myocardium
in SDF-1-, HGF- and LIF-dependent manner
Kucia, Circ Res 2004951190
12
Kucia, Circ Res 2004951191
13
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
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 LVEF40 (PRIMARY PCI lt12 hrs.)
randomization
MRI, LV-ANGIO, ECHO, CONTRAST ECHO,
CARDIOPULMONARY EXERCISE TEST
BMCells TREATMENT
CONTROL
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
CXCR4CD45-
CXCR4CD45
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-1lin-CD45
Sca-1lin-CD45-
CD45 APC-Cy7
20
Very Small Embryonic Like (VSEL) Stem Cell
Hematopoietic Stem Cell
Sca-1lin-CD45
Sca-1lin-CD45-
Leukemia 2006,20857-869
21
RQ-PCR analysis in Sca-1lin-CD45- cells
TCSC markers Sca-1lin-CD45 Sca-1lin-CD45-
cardiac Nsx2.5/Csx 2.05 0.12 98.63 7.93
cardiac GATA-4 2.74 0.41 268.63 31.42
endothelium VE-cadherin 1.05 0.38 142.36 12.49
Leukemia 2006,20857-869
22
AP staining on ES-D3 cell-derived embryonic bodies
AP staining on VSEL derived embryonic like bodies
SSEA-1
Oct4
Nanog
Leukemia 2006,20857-869
23
b myosin heavy chain
troponin I
Kucia, Circ Res 2004951190
Leukemia 2006, 20, 18- 28
24
Transcriptional profile of VSEL-derived
cardiomyocytes
  • Genes with higher expressionin VSELs
    vs. differentiation series
  • CXCR4,
  • TGFß 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
(No Transcript)
26
Mobilization of HSC and VSEL into peripheral
blood after AMI
Courtesy of MZ Ratajczak
27
CONTROL
0,12
0,08
0,05
STEMI
0,32
0,21
0,06
Massa, Blood 2005,105199
Wojakowski, Circulation 20041103213
28
Fazel, J. Clin. Invest. 20061161865
29
  • 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

30
G-CSF induced mobilization
  • G-CSF and HSC
  • proliferation,
  • differentiation,
  • survival
  • G-CSF and non-HSC cardiomyocytes,
  • endothelial cells,
  • neuronal cells

G-CSF
31
STEMMI
REVIVAL-2
MRI GCSF vs. placebo, pNS
Regional systolic wall thickening GCSF vs.
placebo, pNS
Zohlnhofer et al. JAMA 2006,295,1003
Ripa et al. Circulation 2006,113
32
(No Transcript)
33
Migratory capacity of transplanted progenitor
cells and infarct remodeling
Britten, Circulation 20031082212
34
Migratory activity of nonmobilized and
G-CSF-mobilized EPC
Honold, ATVB 2006262238-2243
35
CELL MOBILIZATION FOR IMPROVEMENT OF LV FUNCTION
  • 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

36
Combination of cytokines in murine model of
reperfused MI
G-CSF G-CSF FL (flt3 ligand) G-CSFSCF
Dawn, B. et al. Circ Res 2006981098
37
lin-/Sca-1/c-kit cells from untreated bone
marrow and peripheral blood
Dawn, B. et al. Circ Res 2006981098
38
COMBINATION OF CYTOKINES
  • improved mobilization
  • qualitative differences in function
  • of mobilized cells (adhesion molecules)
  • higher rate of cardiomyocyte proliferation
  • better LV lunction, reduced remodeling

39
UPREGULATION OF SDF-1
SDF-1
Leukemia 2004, 18 29-40
D
Aicher, Circulation 20061142823
40
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

41
KRAKÓW Marcin Majka Ania Zebzda
LOUISVILLE Mariusz Z. Ratajczak Magdalena
Kucia Janina Ratajczak Ewa Zuba-Surma Ryan Reca
KATOWICE Michal Tendera Pawel Buszman Marek
Król Kasia Maslankiewicz Andrzej Pyrlik Radek
Parma Rafal Wyderka Joanna Ciosek Sebastian
Dworowy Iwona Mróz
BRISTOL Paolo Madeddu Nicole Kraenkel Constanza
Emanueli
SZCZECIN Bogdan Machalinski, Maciek Halasa
42
GOOD THING ABOUT BEING INTERVENTIONAL
CARDIOLOGIST IS TO GET A LOT OF
EXPERIENCE IN HEMATOLOGY
THANK YOU
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