Cardiac Surgery University of Rostock 7. IGES Kongress zum Fortschritt im Gesundheitswesen von morgen 22. October 2009 Wiederherstellung der Herzfunktion durch Stammzelltherapie Prof. Dr. med. Gustav Steinhoff Director Reference and Translation Center of Cardiac Stem Cell Therapy (RTC) and Department of Cardiac Surgery University of Rostock
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Cardiac Surgery
University of Rostock
7. IGES Kongress zum Fortschritt im Gesundheitswesen von morgen
22. October 2009
Wiederherstellung der Herzfunktion durch Stammzelltherapie
Prof. Dr. med. Gustav Steinhoff
Director
Reference and Translation Center of Cardiac Stem Cell Therapy (RTC)
and
Department of Cardiac Surgery
University of Rostock
Cardiac Surgery
University of Rostock
asymmetric
replication
symmetric
replication
Adult stem and precursor cells
Cardiac Surgery
University of Rostock
Embryonic stem cell
Wobus, Wallukat & Hescheler, Differentiation 1991
Primitive
mesenchymal cell
SA node-like cell Ventricular
cardiomyocyte
Atrial-like cell
Cardiac Surgery
University of Rostock
Factors for cardiac differentiation of ES-cells
Srivastava et al. Nature 2006
Cardiac Surgery
University of Rostock
Sources of adult stem cells
Engelmann & Franz Curr. Opinion Mol Ther 2006
Cardiac Surgery
University of Rostock
Adult stem cells – bone marrow source
lifelong regeneration potential
Cardiac Surgery
University of Rostock
Cardiac stem cells
Cardiac Surgery
University of Rostock
The impact of stem cells in the future of cardiac therapies
• Stem cells in heart failure treatment
• Stem cells and bridge-to-recovery/ bridge-to-transplant
• Stem cells and immunomodulation after heart
transplantation
• Cellular chimerism and cellular renewal in heart
transplants
• Summary and outlook
Cardiac Surgery
University of Rostock
Ischemic disease Infarction
„myocardial remodeling“
Heart failure
Stemcells for myocardial repair?
application?type of cells? homing?
Valve disease Myocarditis
transplantationmechanical assist device
drugs
differentiation?
Replacement of heart cells by stem cells
Cardiac Surgery
University of Rostock
mod. Dimmeler et al. JCI 2005
directapplication
mobilization
Cardiac Stem Cell Therapy
Cardiac Surgery
University of Rostock
Cell delivery
Mobilization (G-GSF)
Systemic injection
Intracoronary injection
Local implantation
Action
Homing
Extravasation
Stem / Progenitor Cell
Action
SurgeryCardiology
Problems observed
2001: First clinical stem cell application in heart disease (Strauer, Steinhoff)
Strauer, Düsseldorf
Intravascular application MNC BM 3/2001
Steinhoff, Rostock
Intramyocardial application CD133 BMSC 6/2001
Cardiac Surgery
University of Rostock
Orlic D, Kajstura J, Chimenti S, Jakoniuk I, Anderson SM, Li B, et al. Bone marrow cells regenerate infarcted myocardium.
Nature. 2001 Apr 5;410(6829):701-5.
[
Cardiac Surgery
University of Rostock
Murry CE, Soonpaa MH, Reinecke H, Nakajima H, Nakajima HO, Rubart M, et al. Haematopoietic stem cells do not transdifferentiate
into cardiac myocytes in myocardial infarcts. Nature. 2004 Apr 8;428(6983):664-8.
Cardiac Surgery
University of Rostock
Orlic et al, Nature 2001 Murry et al, Nature 2004 Balsam et al, Nature 2004
Myocardial regeneration by bone marrow stem cells
Fernadez-Avilez et al, Circ Res 2004Kajstura et al, Circ Res 2005
Cardiac Surgery
University of Rostock
Direct injection BMSC:
Tomita et al. & Jia / BMCs
Wang et al. & Chiu / rMSC
Toma et al. & Kessler / hMSC
Orlic et al. & Anversa / Lin -, c-
kit+
Intravenous injection BMSC:
Kocher et al. & Itescu / CD34+
Kuramochi et al. & Ogawa /
CD34+
Ciulla et al. & Rebulla / CD34+
Oh et al. & Schneider / Sca-1+
Bone marrow stem cells integrate in the infarcted heart tissue
Cardiac Surgery
University of Rostock
The paracrine hypothesis replaces the hypothesis of
transdifferentiation
Gnecchi M et al. & Dzau V, FASEB J 20, 661-669 (2006)Grigoropoulos N F, Mathur A. Curr Opinion in Pharmacol. 6:1-7 (2006)
Cardiac Surgery
University of Rostock
Embryonic stem cells
Perez-Terzic, Circ Res. 2003, Hodgson et al, AJP 2004
Cardiac Surgery
University of Rostock
Cardiac Surgery
University of Rostock
True cardiac regeneration with stem-cell therapy will require careful consideration at each step, from isolation of the cells to their stable and safe long-term integration.
Segers & Lee, Nature 451, 937-942(21 February 2008)
Different indications for CD133+ cell transplantation (n >120)
Phase III
Cardiac Surgery
University of Rostock
Standardization and training of clinical procedures
Characterization of CD133+ as a cellular product
Chest midline
Chest anterolateral
AC133AC133AC133AC133AC133AC133AC133AC133
100 – 200 ml bone marrow aspirate
CliniMACS separation
BMNC preparation
CD133+ labelling
Cardiac Surgery
University of Rostock
10
20
30
40
50
60
70
preop discharge 6 months 18 months
LV
EF
(%
)
399
476*508* 486*
Results: LVEF Phase-1
* P < 0.012 vs preop; F=6,03 repeated measures ANOVAD. Zurakowski, Boston
Cardiac Surgery
University of Rostock
Results: Change in LVEF Phase-2
-10
-5
0
5
10
15
20
25
30
dif
fere
nc
e in
LV
EF
(%
)
CABG & CD133+ cells CABG
9.7%
3.4%
p=0.0009
Cardiac Surgery
University of Rostock
CABG+cells: Effect of preoperative LV function Phase-1 and 2
change in LVEF following CABG & CD133+ cells
-10
-5
0
5
10
15
20
25
30
diffe
ren
ce in
LV
EF
(%
)
< 35% > 35%preop LVEF
15.4%
6.5%
p=0.003
Cardiac Surgery
University of Rostock
Results: SPECT Perfusion scintigraphy Phase-2
CABG & CD133+ cells
Cardiac Surgery
University of Rostock
preop 6 months 18 months 41 months
LV
ED
V in
ml
0
50
100
150
200
250
300
Stem cell group (n=15)
Controll group (n=11)
*
Left ventricular volume
Cardiac Surgery
University of Rostock
Current status
• A Phase-I clinical feasibility and safety study in 15 CABG patients showed that intramyocardial injection of autologous CD133+ bone marrow cells was not associated with cell-related complications in longterm analysis 1,2.
• In a subsequent Phase-II randomized, controlled, and prospective clinical trial in 40 patients, CABG & intramyocardial injection of CD133+ bone marrow cells resulted in better LV ejection fraction and perfusion than CABG only 3. Longterm safety of the treatment could be confirmed 4.
• Phase-III clinical study investigation (multicentre double-blinded randomized trial) is planned to start in 2009 for definitive clinical introduction in the treatment of chronic ischemia after myocardial infarction.
1 Stamm et al. Autologous bone marrow stem-cell transplantation for myocardial regeneration. Lancet, 361(9351);45-6; 2003
2 Stamm et al. CABG and bone marrow stem cell transplantation after myocardial infarction. Thorac Cardiov Surg, 52(3):152-8; 2004
3 Stamm et al. Intramyocardial delivery of CD133+ bone marrow cells and coronary artery bypass grafting for chronic ischemic heart