bone marrow-derived stem cells progenitor cells

bone marrow-derived stem cells progenitor cells 2001 1

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+ CD34+ - 2 VEGFR-2 KDR flk-1 progenitor cell mononuclear cell 2 98 9

< 0.05% cytokines stromal cell derived factor-1 SDF-1 Homing growth factor 1 3~5 MMP-9 3 1. 3 3

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 4 98 9

LVEF 48.9% LVEF>48.9% TOPCARE-AMI trial 7 4-14 24 8 REPAIR-AMI 4 4-8 reperfusion injury CD34+ CD133+ BOOST trial TOPCARE-AMI trial 5

REPAIR-AMI trial paracrine effect 3-3.66% 2. 4 6 98 9

1 2 3 1. Asahara T, Murohara T, Sullivan A, et al. Isolation of putative progenitor endothelial cells for angiogenesis. Science 1997;275:964-7. 2. Folkman J. Angiogenesis in cancer, vascular, rheumatoid and other disease. Nat Med 1995;1: 27-31. 3. 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;29:1179-84. 4. Dimmeler S, Burchfield J, Zeiher AM. Cell-based therapy of myocardial infarction. Arterioscler Thromb Vasc Biol 2008;28:208-16. 5. 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;355:1210-21. 6. 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;39:150-8. 7. 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;44:1690-9. 8. 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;367:113-21. 7

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- 28 + Regional contractility (LVA) Circulation. 2002 n=40) vs ctrl. overnight teflon Endsystolic volume (LVA) Perfusion (Szinti) TOPCARE AMI. n=59 4.9 CPC 250 ml/3 day culture 16 + Global contractility Circulation. 2002/2003 (LVA/MRI) JACC. 2004 BMC 50 ml/ficoll - 213 Endsystolic volume same day (LVA/MRI) Viability (MRI) Flow reserve (Doppler) Fernandez-Aviles. 20 13.5 BMC 50 ml Ficoll - 78 + Global contractility Circ Res. 2004 overnightteflon (MRI) End systolic volume (MRI) Ruan et al. 10 vs 10 0 BMC vs saline + Global contractility Chin Med J. 2005 (rand.) (LVA) Bartunek et al. 12 14 CD133+BMC Mouse antibody Stenosis? Global contractility Circ. 2005 (LVA) Chen et al. 34 vs 35 18 B-MSC vs 10 day culture + Global contractility Am J Cardiol. 2004 control (LVA) 8 98 9

Randomized trials Single/2 Center(s) BOOST 60 4.8 BMC vs Gelatine polysuccinate - 2460 + 6 months: rand. control same day infusion global contractility (MRI) 1.1 rand. Lancet 2004/Circ 2006 18 months: no significant difference (MRI) Eur Heart J 2006 18 months: diastolic dysfunction (Echo) Janssens et al. 67 <24h BMC vs Ficoll density gradient 304 + Global contractility: Lancet. 2006 i.c. placebo centrifugation - few no change hours after acute PCI 1:1 rand. Infarct size (MRI) ASTAMI New Engl 100 6 BMC vs Lymphoprep TM - 87 + Global contractility: J Med. 2006 rand. control next day infusion no change 1:1 rand. Multicenter-Placebo controlled, double-blind REPAIR - AMI 204 4 BMC vs Ficol density gradient 234 + Global contractility i.c. placebo centrifugation -same or (QLVA) next day infusion New Engl J Med. 1:1 rand. Adverse remodeling 2006 EHJ. 2006 Clinical outcome Circulation. 2007 Flow reserve 9