bone marrow-derived stem cells progenitor cells

Transcription

1 bone marrow-derived stem cells progenitor cells

2 embryonic stem cells adult stem cells tissue-resident stem cells Hematopoietic stem cells side-population cells Mesenchymal stem cells stromal cells Multipotential adult progenitor cells bone marrow-derived mononuclear cells 2-4% < 0.1% side population cells G-CSF CD34+ CD34+ endothelial progenitor cells 1 hemangioblasts CD133+ CD VEGFR-2 KDR flk-1 progenitor cell mononuclear cell

3 < 0.05% cytokines stromal cell derived factor-1 SDF-1 Homing growth factor 1 3~5 MMP

4 mesoangioblasts Mesoangioblasts VEGFR-2 mesoangioblasts cardiac stem cells C-kit+ Sca-1+ side population cells SP Islet-1 6-9% 4-6 Phase I/II REPAIR-AMI trial 5 Bone marrow-derived mononuclear cells 5.5% placebo medium 3% end-systolic left ventricular volumes ASTAMI trial 6 ASTAMI trial Table 1 REPAIR-AMI trial

5 LVEF 48.9% LVEF>48.9% TOPCARE-AMI trial REPAIR-AMI reperfusion injury CD34+ CD133+ BOOST trial TOPCARE-AMI trial 5

6 REPAIR-AMI trial paracrine effect %

7 Asahara T, Murohara T, Sullivan A, et al. Isolation of putative progenitor endothelial cells for angiogenesis. Science 1997;275: Folkman J. Angiogenesis in cancer, vascular, rheumatoid and other disease. Nat Med 1995;1: Huang PH, Chen YH, Wang CH, et al. Matrix metalloproteinase-9 is essential for ischemiainduced neovascularization by modulating the function and behaviors of bone marrow-derived, circulating endothelial progenitor cells. Arterioscler Thromb Vasc Biol 2009;29: Dimmeler S, Burchfield J, Zeiher AM. Cell-based therapy of myocardial infarction. Arterioscler Thromb Vasc Biol 2008;28: Schächinger V, Erbs S, Elsässer A, et al. REPAIR- AMI Investigators. Intracoronary bone marrowderived progenitor cells in acute myocardial infarction. N Engl J Med 2006;355: Lunde K, Solheim S, Aakhus S, et al. Autologous stem cell transplantation in acute myocardial infarction: the ASTAMI randomized controlled trial. Intracoronary transplantation of autologous mononuclear bone marrow cells, study design and safety aspects. Scand Cardiovasc J 2005;39: Schächinger V, Assmus B, Britten MB, et al. Transplantation of progenitor cells and regeneration enhancement in acute myocardial infarction: final one-year results of the TOPCARE-AMI Trial. J Am Coll Cardiol 2004;44: Janssens S, Dubois C, Bogaert J, et al. Autologous bone marrow-derived stem-cell transfer in patients with ST-segment elevation myocardial infarction: double-blind, randomized controlled trial. Lancet 2006;367:

8 Table 1. Clinical trials in patients with acute myocardial infarction 4 Study Patient No. Days after Cell Type Cell Preparation Cell No. Safety Myocardial Function AMI (x106) Pilot trials (Phase I/II) Strauer et al. n=10 (Nov 03: 8 BMC 40 ml Ficoll Regional contractility (LVA) Circulation n=40) vs ctrl. overnight teflon Endsystolic volume (LVA) Perfusion (Szinti) TOPCARE AMI. n= CPC 250 ml/3 day culture 16 + Global contractility Circulation. 2002/2003 (LVA/MRI) JACC BMC 50 ml/ficoll Endsystolic volume same day (LVA/MRI) Viability (MRI) Flow reserve (Doppler) Fernandez-Aviles BMC 50 ml Ficoll Global contractility Circ Res overnightteflon (MRI) End systolic volume (MRI) Ruan et al. 10 vs 10 0 BMC vs saline + Global contractility Chin Med J (rand.) (LVA) Bartunek et al CD133+BMC Mouse antibody Stenosis? Global contractility Circ (LVA) Chen et al. 34 vs B-MSC vs 10 day culture + Global contractility Am J Cardiol control (LVA)

9 Randomized trials Single/2 Center(s) BOOST BMC vs Gelatine polysuccinate months: rand. control same day infusion global contractility (MRI) 1.1 rand. Lancet 2004/Circ months: no significant difference (MRI) Eur Heart J months: diastolic dysfunction (Echo) Janssens et al. 67 <24h BMC vs Ficoll density gradient Global contractility: Lancet i.c. placebo centrifugation - few no change hours after acute PCI 1:1 rand. Infarct size (MRI) ASTAMI New Engl BMC vs Lymphoprep TM Global contractility: J Med rand. control next day infusion no change 1:1 rand. Multicenter-Placebo controlled, double-blind REPAIR - AMI BMC vs Ficol density gradient Global contractility i.c. placebo centrifugation -same or (QLVA) next day infusion New Engl J Med. 1:1 rand. Adverse remodeling 2006 EHJ Clinical outcome Circulation Flow reserve 9