Advertisement

Bone marrow and circulating stem/progenitor cells for regenerative cardiovascular therapy

  • Mohamad Amer Alaiti
    Affiliations
    Division of Cardiovascular Medicine, Harrington-McLaughlin Heart and Vascular Institute, University Hospitals, Case Western Reserve University, Cleveland, Ohio
    Search for articles by this author
  • Masakazu Ishikawa
    Affiliations
    Department of Orthopedic Surgery, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan
    Search for articles by this author
  • Marco A. Costa
    Correspondence
    Reprint requests: Marco A. Costa, MD, PhD, Division of Cardiovascular Medicine, Harrington-McLaughlin Heart and Vascular Institute, University Hospitals, Case Western Reserve University, 11100 Euclid Ave. LKS 3001, Cleveland, OH 44106-5038.
    Affiliations
    Division of Cardiovascular Medicine, Harrington-McLaughlin Heart and Vascular Institute, University Hospitals, Case Western Reserve University, Cleveland, Ohio
    Search for articles by this author
      Cardiovascular disease is the leading cause of death and disability in the Western world. In addition to the advancement of current therapeutic approaches to reduce the associated morbidity and mortality, regenerative medicine and cell-based therapy have been areas of continuous investigation. Circulating and bone-marrow-derived stem or endothelial progenitor cells are an attractive source for regenerative therapy in the cardiovascular field. In this review, we highlight the advantages and limitations of this approach with a focus on key observations from animal studies and clinical trials.

      Abbreviations:

      BM (bone marrow), CAD (coronary artery disease), CD34 (cluster of differentiation 34), CFU (colony-forming unit), CVD (cardiovascular disease), DM (diabetes mellitus), eNOS (endothelial nitric oxide synthase), EF (ejection fraction), EPC (endothelial progenitor cells), GCSF (granulocyte colony stimulating factor), HSC (hematopoetic stem cell), LV (left ventricular), LVESV (left ventricular end systolic volume), MI (myocardial infarction), MNC (mononuclear stem cell), MRI (magnetic resonance imaging), PB (peripheral blood), LVEDV (left ventricular end diastolic volume), CABG (coronary artery bypass graft surgery), CLI (critical limb ischemia)
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Translational Research
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Yusuf S.
        • Reddy S.
        • Ounpuu S.
        • et al.
        Global burden of cardiovascular diseases: part I: general considerations, the epidemiologic transition, risk factors, and impact of urbanization.
        Circulation. 2001; 104: 2746-2753
        • Lopez A.D.
        • Mathers C.D.
        • Ezzati M.
        • et al.
        Global and regional burden of disease and risk factors, 2001: systematic analysis of population health data.
        Lancet. 2006; 367: 1747-1757
        • Folkman J.
        • Shing Y.
        Angiogenesis.
        J Biol Chem. 1992; 267: 10931-10934
        • Risau W.
        • Sariola H.
        • Zerwes H.G.
        • et al.
        Vasculogenesis and angiogenesis in embryonic-stem-cell-derived embryoid bodies.
        Development. 1988; 102: 471-478
        • Asahara T.
        • Murohara T.
        • Sullivan A.
        • et al.
        Isolation of putative progenitor endothelial cells for angiogenesis.
        Science. 1997; 275: 964-967
        • Shi Q.
        • Rafii S.
        • Wu M.H.
        • et al.
        Evidence for circulating bone marrow-derived endothelial cells.
        Blood. 1998; 92: 362-367
        • Yin A.H.
        • Miraglia S.
        • Zanjani E.D.
        • et al.
        AC133, a novel marker for human hematopoietic stem and progenitor cells.
        Blood. 1997; 90: 5002-5012
        • Timmermans F.
        • Plum J.
        • Yöder M.C.
        • et al.
        Endothelial progenitor cells: identity defined?.
        J Cell Mol Med. 2009; 13: 87-102
        • Ingram D.A.
        • Caplice N.M.
        • Yoder M.C.
        • et al.
        Unresolved questions, changing definitions, and novel paradigms for defining endothelial progenitor cells.
        Blood. 2005; 106: 1525-1531
        • Massa M.
        • Rosti V.
        • Ferrario M.
        • et al.
        Increased circulating hematopoietic and endothelial progenitor cells in the early phase of acute myocardial infarction.
        Blood. 2005; 105: 199-206
        • Shintani S.
        • Murohara T.
        • Ikeda H.
        • et al.
        Mobilization of endothelial progenitor cells in patients with acute myocardial infarction.
        Circulation. 2001; 103: 2776-2779
        • Leone A.M.
        • Rutella S.
        • Bonanno G.
        • et al.
        Mobilization of bone marrow-derived stem cells after myocardial infarction and left ventricular function.
        Eur Heart J. 2005; 26: 1196-1204
        • Valgimigli M.
        • Rigolin G.M.
        • Fucili A.
        • et al.
        CD34_ and endothelial progenitor cells in patients with various degrees of congestive heart failure.
        Circulation. 2004; 110: 1209-1212
        • Nonaka-Sarukawa M.
        • Yamamoto K.
        • Aoki H.
        • et al.
        Circulating endothelial progenitor cells in congestive heart failure.
        Int J Cardiol. 2007; 119: 344-348
        • Shmilovich H.
        • Deutsch V.
        • Roth A.
        • et al.
        Circulating endothelial progenitor cells in patients with cardiac syndrome X.
        Heart. 2007; 93: 1071-1076
        • Vasa M.
        • Fichtlscherer S.
        • Adler K.
        • et al.
        Increase in circulating endothelial progenitor cells by statin therapy in patients with stable coronary artery disease.
        Circulation. 2001; 103: 2885-2890
        • Leone A.M.
        • Rutella S.
        • Giannico M.B.
        • et al.
        Effect of intensive vs standard statin therapy on endothelial progenitor cells and left ventricular function in patients with acute myocardial infarction: statins for regeneration after acute myocardial infarction and PCI (STRAP) trial.
        Int J Cardiol. 2008; 130: 457-462
        • Bahlmann F.H.
        • deGroot K.
        • Spandau J.M.
        • et al.
        Erythropoietin regulates endothelial progenitor cells.
        Blood. 2004; 103: 921-926
        • Strehlow K.
        • Werner N.
        • Berweiler J.
        • et al.
        Estrogen increases bone marrow-derived endothelial progenitor cell production and diminishes neointima formation.
        Circulation. 2003; 107: 3059-3065
        • Wang C.H.
        • Ting M.K.
        • Verma S.
        • et al.
        Pioglitazone increases the numbers and improves the functional capacity of endothelial progenitor cells in patients with diabetes mellitus.
        Am Heart J. 2006; 152: e1-e8
        • Humpert P.M.
        • Neuwirth R.
        • Battista M.J.
        • Voronko
        • et al.
        SDF-1 genotype influences insulin-dependent mobilization of adult progenitor cells in type 2 diabetes.
        Diabetes Care. 2005; 28: 934-936
        • Thum T.
        • Hoeber S.
        • Froese S.
        • et al.
        Age dependent impairment of endothelial progenitor cells is corrected by growth-hormone-mediated increase of insulin-like growth-factor-1.
        Circ Res. 2007; 100: 434-443
        • Thum T.
        • Fleissner F.
        • Klink I.
        • et al.
        Growth hormone treatment improves markers of systemic nitric oxide bioavailability via insulin-like growth factor-I.
        J Clin Endocrinol Metab. 2007; 92: 4172-4179
        • DiFabio J.M.
        • Thomas G.R.
        • Zucco L.
        • et al.
        Nitroglycerin attenuates human endothelial progenitor cell differentiation, function, and survival.
        J Pharmacol Exp Ther. 2006; 318: 117-123
        • Werner N.
        • Kosiol S.
        • Schiegl T.
        • et al.
        Circulating endothelial progenitor cells and cardiovascular outcomes.
        N Engl J Med. 2005; 353: 999-1007
        • Rehman J.
        • Li J.
        • Parvathaneni L.
        • et al.
        Exercise acutely increases circulating endothelial progenitor cells and monocyte-/macrophage-derived angiogenic cells.
        J Am Coll Cardiol. 2004; 43: 2314-2318
        • Laufs U.
        • Werner N.
        • Link A.
        • et al.
        Physical training increases endothelial progenitor cells, inhibits neointima formation, and enhances angiogenesis.
        Circulation. 2004; 109: 220-226
        • Huang P.H.
        • Chen Y.H.
        • Chen Y.L.
        • et al.
        Vascular endothelial function and circulating endothelial progenitor cells in patients with cardiac syndrome X.
        Heart. 2007; 93: 1064-1070
        • Laufs U.
        • Urhausen A.
        • Werner N.
        • et al.
        Running exercise of different duration and intensity: effect on endothelial progenitor cells in healthy subjects.
        Eur J Cardiovasc Prev Rehabil. 2005; 12: 407-414
        • Adams V.
        • Lenk K.
        • Linke A.
        • et al.
        Increase of circulating endothelial progenitor cells in patients with coronary artery disease after exercise-induced ischemia.
        Arterioscler Thromb Vasc Biol. 2004; 24: 684-690
        • Kissel C.K.
        • Lehmann R.
        • Assmus B.
        • et al.
        Selective functional exhaustion of hematopoietic progenitor cells in the bone marrow of patients with postinfarction heart failure.
        J Am Coll Cardiol. 2007; 49: 2341-2349
        • Pirro M.
        • Schillaci G.
        • Menecali C.
        • et al.
        Reduced number of circulating endothelial progenitors and HOXA9 expression in CD34+ cells of hypertensive patients.
        J Hypertens. 2007; 25: 2093-2099
        • Fadini G.P.
        • de Kreutzenberg S.V.
        • Coracina A.
        • et al.
        Circulating CD34+ cells, metabolic syndrome, and cardiovascular risk.
        Eur Heart J. 2006; 27: 2247-2255
        • Schmidt-Lucke C.
        • Rossig L.
        • Fichtlscherer S.
        • et al.
        Reduced number of circulating endothelial progenitor cells predicts future cardiovascular events: proof of concept for the clinical importance of endogenous vascular repair.
        Circulation. 2005; 111: 2981-2987
        • Hughes A.
        • Coady E.
        • Raynor S.
        • et al.
        Reduced endothelial progenitor cells in European and south Asian men with atherosclerosis.
        Eur J Clin Invest. 2007; 37: 35-41
        • Eizawa T.
        • Ikeda U.
        • Murakami Y.
        • et al.
        Decrease in circulating endothelial progenitor cells in patients with stable coronary artery disease.
        Heart. 2004; 90: 685-686
        • Fadini G.P.
        • Pucci L.
        • Vanacore R.
        • et al.
        Glucose tolerance is negatively associated with circulating progenitor cell levels.
        Diabetologia. 2007; 50: 2156-2163
        • Fadini G.P.
        • Coracina A.
        • Baesso I.
        • et al.
        Peripheral blood CD34+KDR+ endothelial progenitor cells are determinants of subclinical atherosclerosis in a middle-aged general population.
        Stroke. 2006; 37: 2277-2282
        • Fadini G.P.
        • Sartore S.
        • Albiero M.
        • et al.
        Number and function of endothelial progenitor cells as a marker of severity for diabetic vasculopathy.
        Arterioscler ThrombVasc Biol. 2006; 26: 2140-2146
        • Fadini G.P.
        • Miorin M.
        • Facco M.
        • et al.
        Circulating endothelial progenitor cells are reduced in peripheral vascular complications of type 2 diabetes mellitus.
        J Am Coll Cardiol. 2005; 45: 1449-1457
        • Vasa M.
        • Fichtlscherer S.
        • Aicher A.
        • et al.
        Number and migratory activity of circulating endothelial progenitor cells inversely correlate with risk factors for coronary artery disease.
        Circ Res. 2001; 89: E1-E7
        • Kondo T.
        • Hayashi M.
        • Takeshita K.
        • et al.
        Smoking cessation rapidly increases circulating progenitor cells in peripheral blood in chronic smokers.
        Arterioscler Thromb Vasc Biol. 2004; 24: 1442-1447
        • Scheubel R.J.
        • Zorn H.
        • Silber R.E.
        • et al.
        Age-dependent depression in circulating endothelial progenitor cells in patients undergoing coronary artery bypass grafting.
        J Am Coll Cardiol. 2003; 42: 2073-2080
        • Taguchi A.
        • Matsuyama T.
        • Moriwaki H.
        • et al.
        Circulating CD34-positive cells provide an index of cerebrovascular function.
        Circulation. 2004; 109: 2972-2975
        • Landmesser U.
        • Bahlmann F.
        • Mueller M.
        • et al.
        Simvastatin versus ezetimibe: pleiotropic and lipid-lowering effects on endothelial function in humans.
        Circulation. 2005; 111: 2356-2363
        • Bahlmann F.H.
        • deGroot K.D.
        • Mueller O.
        • Hertel B.
        • Haller H.
        • Flisser D.
        Stimulation of endothelial progenitor cells. A new putative therapeutic effect of angiotensin II receptor antagonists.
        Hypertension. 2005; 45: 526-529
        • Min T.Q.
        • Zhu C.J.
        • Xiang W.X.
        • Hui Z.J.
        • Peng S.Y.
        Improvement in endothelial progenitor cells from peripheral blood by ramipril therapy in patients with stable coronary artery disease.
        Cardiovasc Drugs Ther. 2004; 18: 203-209
        • Pistrosch F.
        • Herbrig K.
        • Oelschlaegel U.
        • et al.
        PPARgamma-agonist rosiglitazone increases number and migratory activity of cultured endothelial progenitor cells.
        Atherosclerosis. 2005; 183: 163-167
        • Akita T.
        • Murohara T.
        • Ikeda H.
        • et al.
        Hypoxic preconditioning augments efficacy of human endothelial progenitor cells for therapeutic neovascularization.
        Lab Invest. 2003; 83: 65-73
        • Loomans C.J.M.
        • deKoening E.J.P.
        • Staal F.J.T.
        • et al.
        Endothelial progenitor cell dysfunction. A novel concept in the pathogenesis of vascular complications of type I diabetes.
        Diabetes. 2004; 53: 195-199
        • Tepper O.M.
        • Galiano R.D.
        • Capla J.M.
        • et al.
        Human endothelial progenitor cells from type II diabetes exhibit impaired proliferation, adhesion, and incorporation into vascular structures.
        Circulation. 2002; 106: 2781-2786
        • Chen J.Z.
        • Zhang F.R.
        • Tao Q.M.
        • Wang X.X.
        • Zhu J.H.
        Number and activity of endothelial progenitor cells from peripheral blood in patients with hypercholesterolaemia.
        Clin Sci (Lond). 2004; 107: 273-280
        • Chen J.Z.
        • Zhu J.H.
        • Wang X.X.
        • et al.
        Effects of homocysteine on number and activity of endothelial progenitor cells from peripheral blood.
        J Mol Cell Cardiol. 2004; 36: 233-239
        • George J.
        • Goldstein E.
        • Abashidze S.
        • et al.
        Circulating endothelial progenitor cells in patients with unstable angina: association with systemic inflammation.
        Eur Heart J. 2004; 25: 1003-1008
        • Michowitz Y.
        • Goldstein E.
        • Wexler D.
        Circulating endothelial progenitor cells and clinical outcome in patients with congestive heart failure.
        Heart. 2007; 93: 1046-1050
        • Heeschen C.
        • Lehman R.
        • Honold J.
        • et al.
        Profoundly reduced neovascularization capacity of bone marrow mononuclear cells derived from patients with chronic ischemic heart disease.
        Circulation. 2004; 109: 1615-1622
        • Kunz G.
        • Liang G.
        • Cuculi F.
        • et al.
        circulating endothelial progenitor cells predict coronary artery disease severity.
        Am Heart J. 2006; 152: 190-195
        • Simper D.
        • Wang S.
        • Deb A.
        • et al.
        Endothelial progenitor cells are decreased in blood of cardiac allograft patients with vasculopathy and endothelial cells of non cardiac origin are enriched in transplant atherosclerosis.
        Circulation. 2003; 107: 143-149
        • Humpert P.M.
        • Djuric Z.
        • Zeuge U.
        • et al.
        Insulin stimulates the clonogenic potential of angiogenic endothelial progenitor cells by IGF-1 receptor-dependent signaling.
        Mol Med. 2008; 14: 301-308
        • Hill J.M.
        • Zalos G.
        • Halcox J.P.
        • et al.
        Circulating endothelial progenitor cells, vascular function, and cardiovascular risk.
        N Engl J Med. 2003; 348: 593-600
        • Dimmeler S.
        • Aicher A.
        • Vasa M.
        • et al.
        HMG-CoA reductase inhibitors (statins) increase endothelial progenitor cells via the PI 3-kinase/Akt pathway.
        J Clin Invest. 2001; 108: 391-397
        • Assmus B.
        • Urbich C.
        • Aicher A.
        • et al.
        HMG-CoA reductase inhibitors reduce senescence and increase proliferation of endothelial progenitor cells via regulation of cell cycle regulatory genes.
        Circ Res. 2003; 92: 1049-1055
        • Imanishi T.
        • Moriwaki C.
        • Hano T.
        • et al.
        Endothelial progenitor cell senescence is accelerated in both experimental hypertensive rats and patients with essential hypertension.
        J Hypertens. 2005; 23: 1831-1837
        • Heiss C.
        • Keymel S.
        • Niesler U.
        • et al.
        Impaired progenitor cell activity in age-related endothelial dysfunction.
        J Am Coll Cardiol. 2005; 45: 1441-1448
        • Michaud S.E.
        • Dussault S.
        • Haddad P.
        • et al.
        Circulating endothelial progenitor cells from healthy smokers exhibit impaired functional activities.
        Atherosclerosis. 2006; 187: 423-432
        • Walter D.H.
        • Rittig K.
        • Bahlmann F.H.
        • et al.
        Statin therapy accelerates reendothelialization. A novel effect involving mobilization and incorporation of bone marrow–derived endothelial progenitor cells.
        Circulation. 2002; 105: 3017-3024
        • Yamamoto K.
        • Takahashi T.
        • Asahara T.
        • et al.
        Proliferation, differentiation, and tube formation by endothelial progenitor cells in response to shear stress.
        J Appl Physiol. 2003; 95: 2081-2088
        • Imanishi T.
        • Hano T.
        • Nishio I.
        Angiotensin II accelerates endothelial progenitor cell senescence through induction of oxidative stress.
        J Hypertens. 2005; 23: 97-104
        • Gensch C.
        • Clever Y.P.
        • Werner C.
        • et al.
        The PPARgamma agonist pioglitazone increases neoangiogenesis and prevents apoptosis of endothelial progenitor cells.
        Atherosclerosis. 2007; 192: 67-74
        • Spyridopoulos I.
        • Haendeler J.
        • Urbich C.
        • et al.
        Statins enhance migratory capacity by upregulation of the telomere repeat-binding factor TRF2 in endothelial progenitor cells.
        Circulation. 2004; 110: 3136-3142
        • Strauer B.E.
        • Brehm M.
        • Zeus T.
        • et al.
        Repair of infarcted myocardium by autologous intracoronary mononuclear bone marrow cell transplantation in humans.
        Circulation. 2002; 106: 1913-1918
        • Lunde K.
        • Solheim S.
        • Aakhus S.
        • et al.
        Intracoronary injection of mononuclear bone marrow cells in acute myocardial infarction.
        N Eng J Med. 2006; 355: 1199-1209
        • Lunde K.
        • Solheim S.
        • Forfang K.
        • et al.
        Anterior myocardial infarction with acute percutaneous coronary intervention and intracoronary injection of autologous mononuclear bone marrow cells: safety, clinical outcome, and serial changes in left ventricular function during 12-months’ follow-up.
        J Am Coll Cardiol. 2008; 51: 674-676
        • Beitnes J.O.
        • Hopp E.
        • Lunde K.
        • et al.
        Long-term results after intracoronary injection of autologous mononuclear bone marrow cells in acute myocardial infarction: the ASTAMI randomised, controlled study.
        Heart. 2009; 95: 1983-1989
        • Schachinger V.
        • Erbs S.
        • Elsasser A.
        • et al.
        Intracoronary bone marrow-derived progenitor cells in acute myocardial infarction.
        N Eng J Med. 2006; 355: 1210-1221
        • Schachinger V.
        • Erbs S.
        • Elsasser A.
        • et al.
        Improved clinical outcome after intracoronary administration of bone-marrow-derived progenitor cells in acute myocardial infarction: final 1-year results of the REPAIR-AMI trial.
        Eur Heart J. 2006; 27: 2775-2783
        • Assmus B.
        • Rolf A.
        • Erbs S.
        • et al.
        Clinical outcome 2 years after intracoronary administration of bone marrow-derived progenitor cells in acute myocardial infarction.
        Circ Heart Fail. 2010; 3: 89-96
        • Wollert K.C.
        • Meyer G.P.
        • Lotz J.
        • et al.
        Intracoronary autologous bone-marrow cell transfer after myocardial infarction: the BOOST randomised controlled clinical trial.
        Lancet. 2004; 364: 141-148
        • Meyer G.P.
        • Wollert K.C.
        • Lotz J.
        • et al.
        Intracoronary bone marrow cell transfer after myocardial infarction: eighteen months’ follow-up data from the randomized, controlled BOOST (BOne marrOw transfer to enhance ST-elevation infarct regeneration) trial.
        Circulation. 2006; 113: 1287-1294
        • Janssens S.
        • Dubois C.
        • Bogaert J.
        • et al.
        Autologous bone marrow-derived stem-cell transfer in patients with STsegment elevation myocardial infarction: double-blind, randomised controlled trial.
        Lancet. 2006; 367: 113-121
        • Meluzin J.
        • Janousek S.
        • Mayer J.
        • et al.
        Three-, 6-, and 12-month results of autologous transplantation of mononuclear bone marrow cells in patients with acute myocardial infarction.
        Int J Cardiol. 2008; 128: 185-192
        • Meluzin J.
        • Mayer J.
        • Groch L.
        • et al.
        Autologous transplantation of mononuclear bone marrow cells in patients with acute myocardial infarction: the effect of the dose of transplanted cells on myocardial function.
        Am Heart J. 2006; 152: e9-15
        • Ge J.
        • Li Y.
        • Qian J.
        • et al.
        Efficacy of emergent transcatheter transplantation of stem cells for treatment of acute myocardial infarction (TCT-STAMI).
        Heart (British Cardiac Society). 2006; 92: 1764-1767
        • Yousef M.
        • Schannwell C.M.
        • Köstering M.
        • et al.
        The BALANCE Study: clinical benefit and long-term outcome after intracoronary autologous bone marrow cell transplantation in patients with acute myocardial infarction.
        J Am Coll Cardiol. 2009; 53: 2262-2269
        • Fernandez-Aviles F.
        • San Roman J.A.
        • Garcia-Frade J.
        • et al.
        Experimental and clinical regenerative capability of human bone marrow cells after myocardial infarction.
        Circ Res. 2004; 95: 742-748
        • Mocini D.
        • Staibano M.
        • Mele L.
        • Giannantoni P.
        • Menichella G.
        • Colivicchi F.
        • et al.
        Autologous bone marrow mononuclear cell transplantation in patients undergoing coronary artery bypass grafting.
        Am Heart J. 2006; 151: 192-197
        • Bartunek J.
        • Vanderheyden M.
        • Vandekerckhove B.
        • et al.
        Intracoronary injection of CD133-positive enriched bone marrow progenitor cells promotes cardiac recovery after recent myocardial infarction: feasibility and safety.
        Circulation. 2005; 112: I178-I183
        • Stamm C.
        • Westphal B.
        • Kleine H.D.
        • et al.
        Autologous bone-marrow stem-cell transplantation for myocardial regeneration.
        Lancet. 2003; 361: 45-46
        • Stamm C.
        • Kleine H.D.
        • Choi Y.H.
        • et al.
        Intramyocardial delivery of CD133+ bone marrow cells and coronary artery bypass grafting for chronic ischemic heart disease: safety and efficacy studies.
        J Thor Cardiovasc Surg. 2007; 133: 717-725
        • Ahmadi H.
        • Baharvand H.
        • Ashtiani S.K.
        • et al.
        Safety analysis and improved cardiac function following local autologous transplantation of CD133(+) enriched bone marrow cells after myocardial infarction.
        Curr Neurovasc Res. 2007; 4: 153-160
        • Li Z.Q.
        • Zhang M.
        • Jing Y.Z.
        • et al.
        The clinical study of autologous peripheral blood stem cell transplantation by intracoronary infusion in patients with acute myocardial infarction (AMI).
        Int J Cardiol. 2007; 115: 52-56
        • Tatsumi T.
        • Ashihara E.
        • Yasui T.
        • et al.
        Intracoronary transplantation of non-expanded peripheral blood-derived mononuclear cells promotes improvement of cardiac function in patients with acute myocardial infarction.
        Circ J. 2007; 71: 1199-1207
        • Gyöngyösi M.
        • Lang I.
        • Dettke M.
        • et al.
        Combined delivery approach of bone marrow mononuclear stem cells early and late after myocardial infarction: the MYSTAR prospective, randomized study.
        Nat Clin Pract Cardiovasc Med. 2009; 6: 70-81
        • Llevadot J.
        • Murasawa S.
        • Kureishi Y.
        • et al.
        HMG-CoA reductase inhibitor mobilizes bone marrow-derived endothelial progenitor cells.
        J Clin Invest. 2001; 108: 399-405
        • Aicher A.
        • Heeschen C.
        • Mildner-Rihm C.
        • et al.
        Essential role of endothelial nitric oxide synthase for mobilization of stem and progenitor cells.
        Nat Med. 2003; 9: 1370-1376
        • Sasaki K.
        • Heeschen C.
        • Aicher A.
        • et al.
        Ex vivo pretreatment of bone marrow mononuclear cells with endothelial NO synthase enhancer AVE9488 enhances their functional activity for cell therapy.
        Proc Natl Acad Sci U S A. 2006; 103: 14537-14541
        • Asahara T.
        • Masuda H.
        • Takahashi T.
        • et al.
        Bone marrow origin of endothelial progenitor cells responsible for postnatal vasculogenesis in physiological and pathological neovascularization.
        Circ Res. 1999; 85: 221-228
        • Jackson K.A.
        • Majka S.M.
        • Wang H.
        • et al.
        Regeneration of ischemic cardiac muscle and vascular endothelium by adult stem cells.
        J Clin Invest. 2001; 107: 1395-1402
        • Yeh E.T.
        • Zhang S.
        • Wu H.D.
        • et al.
        Transdifferentiation of human peripheral blood CD34+-enriched cell population into cardiomyocytes, endothelial cells, and smooth muscle cells in vivo.
        Circulation. 2003; 108: 2070-2073
        • Iwasaki H.
        • Kawamoto A.
        • Ishikawa M.
        • et al.
        Dose-dependent contribution of CD34-positive cell transplantation to concurrent vasculogenesis and cardiomyogenesis for functional regenerative recovery after myocardial infarction.
        Circulation. 2006; 113: 1311-1325
        • Kalka C.
        • Masuda H.
        • Takahashi T.
        • et al.
        Transplantation of ex vivo expanded endothelial progenitor cells for therapeutic neovascularization.
        Proc Natl Acad Sci U S A. 2000; 97: 3422-3427
        • Kawamoto A.
        • Gwon H.C.
        • Iwaguro H.
        • et al.
        Therapeutic potential of ex vivo expanded endothelial progenitor cells for myocardial ischemia.
        Circulation. 2001; 103: 634-637
        • Kocher A.A.
        • Schuster M.D.
        • Szabolcs M.J.
        • et al.
        Neovascularization of ischemic myocardium by human bone-marrow–derived angioblasts prevents cardiomyocyte apoptosis, reduces remodeling and improves cardiac function.
        Nat Med. 2001; 7: 430-436
        • Jackson K.A.
        • Majka S.M.
        • Wang H.
        • et al.
        Regeneration of ischemic cardiac muscle and vascular endothelium by adult stem cells.
        J Clin Invest. 2001; 107: 1395-1402
        • Orlic D.
        • Kajstura J.
        • Chimenti S.
        • et al.
        Bone marrow cells regenerate infarcted myocardium.
        Nature. 2001; 410: 701-705
        • Badorff C.
        • Brandes R.P.
        • Popp R.
        • et al.
        Transdifferentiation of blood-derived human adult endothelial progenitor cells into functionally active cardiomyocytes.
        Circulation. 2003; 107: 1024-1032
        • Balsam L.B.
        • Wagers A.J.
        • Christensen J.L.
        • Kofidis T.
        • Weissman I.L.
        • Robbins R.C.
        Haematopoietic stem cells adopt mature haematopoietic fates in ischaemic myocardium.
        Nature. 2004; 428: 668-673
        • Murry C.E.
        • Soonpaa M.H.
        • Reinecke H.
        • et al.
        Haematopoietic stem cells do not transdifferentiate into cardiac myocytes in myocardial infarcts.
        Nature. 2004; 428: 664-668
        • Nygren J.M.
        • Jovinge S.
        • Breitbach M.
        • et al.
        Bone marrow-derived hematopoietic cells generate cardiomyocytes at a low frequency through cell fusion, but not transdifferentiation.
        Nat Med. 2004; 10: 494-501
        • Dohmann H.F.
        • Perin E.C.
        • Takiya C.M.
        • et al.
        Transendocardial autologous bone marrow mononuclear cell injection in ischemic heart failure: postmortem anatomicopathologic and immunohistochemical findings.
        Circulation. 2005; 112: 521-526
        • Urbich C.
        • Aicher A.
        • Heeschen C.
        • et al.
        Soluble factors released by endothelial progenitor cells promote migration of endothelial cells and cardiac resident progenitor cells.
        J Mol Cell Cardiol. 2005; 39: 733-742
        • Ii M.
        • Nishimura H.
        • Iwakura A.
        • et al.
        Endothelial progenitor cells are rapidly recruited to myocardium and mediate protective effect of ischemic preconditioning via preconditioning via “imported” nitric oxide synthase activity.
        Circulation. 2005; 111: 1114-1120
        • Dai Y.
        • Ashraf M.
        • Zuo S.
        • et al.
        Mobilized bone marrow progenitor cells serve as donors of cytoprotective genes for cardiac repair.
        J Mol Cell Cardiol. 2008; 44: 607-617
        • Zubair A.C.
        • Malik S.
        • Paulsen A.
        • et al.
        Evaluation of mobilized peripheral blood CD34(+) cells from patients with severe coronary artery disease as a source of endothelial progenitor cells.
        Cytotherapy. 2010; 12: 178-189
        • Murasawa S.
        • Llevadot J.
        • Silver M.
        • et al.
        Constitutive human telomerase reverse transcriptase expression enhances regenerative properties of endothelial progenitor cells.
        Circulation. 2002; 106: 1133-1139
        • Thum T.
        • Bauersachs J.
        • Poole-Wilson P.A.
        • et al.
        The dying stem cell hypothesis: immune modulation as a novel mechanism for progenitor cell therapy in cardiac muscle.
        J Am Coll Cardiol. 2005; 46: 1799-1802
        • Assmus B.
        • Schachinger V.
        • Teupe C.
        • et al.
        Transplantation of Progenitor Cells and Regeneration Enhancement in Acute Myocardial Infarction (TOPCARE-AMI).
        Circulation. 2002; 106: 3009-3017
        • Schachinger V.
        • Assmus B.
        • Britten M.B.
        • 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: 1690-1699
        • Tse H.F.
        • Kwong Y.L.
        • Chan J.K.
        • et al.
        Angiogenesis in ischaemic myocardium by intramyocardial autologous bone marrow mononuclear cell implantation.
        Lancet. 2003; 361: 47-49
        • Perin E.C.
        • Dohmann H.F.
        • Borojevic R.
        • et al.
        Transendocardial, autologous bone marrow cell transplantation for severe, chronic ischemic heart failure.
        Circulation. 2003; 107: 2294-2302
        • George J.C.
        Stem cell therapy in acute myocardial infarction: a review of clinical trials.
        Transl Res. 2010; 155: 10-19
        • Schächinger V.
        • Assmus B.
        • Erbs S.
        • et al.
        Intracoronary infusion of bone marrow-derived mononuclear cells abrogates adverse left ventricular remodelling post-acute myocardial infarction: insights from the reinfusion of enriched progenitor cells and infarct remodelling in acute myocardial infarction (REPAIR-AMI) trial.
        Eur J Heart Fail. 2009; 11: 973-979
        • Erbs S.
        • Linke A.
        • SchachingerV
        • et al.
        Restoration of microvascular function in the infarct-related artery by intracoronary transplantation of bone marrow progenitor cells in patients with acute myocardial infarction: the Doppler Substudy of the Reinfusion of Enriched Progenitor Cells and Infarct Remodeling in Acute Myocardial Infarction (REPAIR-AMI) trial.
        Circulation. 2007; 116: 366-374
        • Meyer G.P.
        • Wollert K.C.
        • Lotz J.
        • et al.
        Intracoronary bone marrow cell transfer after myocardial infarction: 5-year follow-up from the randomized-controlled BOOST trial.
        Eur Heart J. 2009; 30: 2978-2984
        • Lunde K.
        • Solheim S.
        • Aakhus S.
        • et al.
        Exercise capacity and quality of life after intracoronary injection of autologous mononuclear bone marrow cells in acute myocardial infarction: results from the Autologous Stem cell Transplantation in Acute Myocardial Infarction (ASTAMI) randomized controlled trial.
        Am Heart J. 2007; 154: e1-e8
        • Lipinski M.J.
        • Biondi-Zoccai G.G.
        • Abbate A.
        • et al.
        Impact of intracoronary cell therapy on left ventricular function in the setting of acute myocardial infarction: a collaborative systematic review and meta-analysis of controlled clinical trials.
        J Am Coll Cardiol. 2007; 50: 1761-1767
        • Martin-Rendon E.
        • Brunskill S.J.
        • Hyde C.J.
        • et al.
        Autologous bone marrow stem cells to treat acute myocardial infarction: a systematic review.
        Eur Heart J. 2008; 29: 1807-1818
        • Abdel-Latif A.
        • Bolli R.
        • Tleyjeh I.M.
        • et al.
        Adult bone marrow-derived cells for cardiac repair: a systematic review and meta-analysis.
        Arch Intern Med. 2007; 167: 989-997
        • Fuchs S.
        • Baffour R.
        • Zhou Y.F.
        • et al.
        Transendocardial delivery of autologous bone marrow enhances collateral perfusion and regional function in pigs with chronic experimental myocardial ischemia.
        J Am Coll Cardiol. 2001; 37: 1726-1732
        • Kudo M.
        • Wang Y.
        • Wani M.A.
        • et al.
        Implantation of bone marrow stem cells reduces the infarction and fibrosis in ischemic mouse heart.
        J Mol Cell Cardiol. 2003; 35: 1113-1119
        • Perin E.C.
        • Dohmann H.F.
        • Borojevic R.
        • et al.
        Improved exercise capacity and ischemia 6 and 12 months after trans-endocardial injection of autologous bone marrow mononuclear cells for ischemic cardiomyopathy.
        Circulation. 2004; 110: II213-II218
        • Tse H.F.
        • Thambar S.
        • Kwong Y.L.
        • et al.
        Prospective randomized trial of direct endomyocardial implantation of bone marrow cells for treatment of severe coronary artery diseases (PROTECT-CAD trial).
        Eur Heart J. 2007; 28: 2998-3005
        • Hendrikx M.
        • Hensen K.
        • Clijsters C.
        • et al.
        Recovery of regional but not global contractile function by the direct intramyocardial autologous bone marrow transplantation: results from a randomized controlled clinical trial.
        Circulation. 2006; 114: I101-I107
        • van Ramshorst J.
        • Bax J.J.
        • Beeres S.L.
        • et al.
        Intramyocardial bone marrow cell injection for chronic myocardial ischemia: a randomized controlled trial.
        JAMA. 2009; 301: 1997-2004
        • Strauer B.E.
        • Brehm M.
        • Zeus T.
        • et al.
        Regeneration of human infarcted heart muscle by intracoronary autologous bone marrow cell transplantation in chronic coronary artery disease: the IACT Study.
        J Am Coll Cardiol. 2005; 46: 1651-1658
        • Assmus B.
        • Honold J.
        • Schachinger V.
        • et al.
        Transcoronary transplantation of progenitor cells after myocardial infarction.
        N Eng J Med. 2006; 355: 1222-1232
        • Losordo D.W.
        • Schatz R.A.
        • White C.J.
        • et al.
        Intramyocardial transplantation of autologous CD34+ stem cells for intractable angina: a phase I/IIa double-blind, randomized controlled trial.
        Circulation. 2007; 115: 3165-3172
        • Losordo D.W.
        • Henry T.
        • Schatz R.A.
        • et al.
        Autologous CD34+ cell therapy for refractory angina: 12 month results of the phase II ACT34-CMI study. Annual Scientific Session of the American Heart Association.
        Circulation. 2009; 120: S1132
        • Fischer-Rasokat U.
        • Assmus B.
        • Seeger F.H.
        • et al.
        A pilot trial to assess potential effects of selective intracoronary bone marrow-derived progenitor cell infusion in patients with nonischemic dilated cardiomyopathy: final 1-year results of the transplantation of progenitor cells and functional regeneration enhancement pilot trial in patients with nonischemic dilated cardiomyopathy.
        Circ Heart Fail. 2009; 2: 417-423
        • Volpi A.
        • Cavalli A.
        • Turato R.
        • et al.
        Incidence and short-term prognosis of late sustained ventricular tachycardia after myocardial infarction: results of the Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico (GISSI-3) Data Base.
        Am Heart J. 2001; 142: 87-92
        • Epstein S.E.
        • Stabile E.
        • Kinnaird T.
        • et al.
        Janus phenomenon: the interrelated tradeoffs inherent in therapies designed to enhance collateral formation and those designed to inhibit atherogenesis.
        Circulation. 2004; 109: 2826-2831
        • Mansour S.
        • Vanderheyden M.
        • De Bruyne B.
        • et al.
        Intracoronary delivery of hematopoietic bone marrow stem cells and luminal loss of the infarct-related artery in patients with recent myocardial infarction.
        J Am Coll Cardiol. 2006; 47: 1727-1730
        • Kang H.J.
        • Kim H.S.
        • Zhang S.Y.
        • et al.
        Effects of intracoronary infusion of peripheral blood stem-cells mobilised with granulocyte-colony stimulating factor on left ventricular systolic function and restenosis after coronary stenting in myocardial infarction: the MAGIC cell randomised clinical trial.
        Lancet. 2004; 363: 751-756
        • Cho H.J.
        • Kim T.Y.
        • Cho H.J.
        • et al.
        The effect of stem cell mobilization by granulocyte-colony stimulating factor on neointimal hyperplasia and endothelial healing after vascular injury with bare-metal versus paclitaxel-eluting stents.
        J Am Coll Cardiol. 2006; 48: 366-374
        • Kang H.J.
        • Lee H.Y.
        • Na S.H.
        • et al.
        Differential effect of intracoronary infusion of mobilized peripheral blood stem cells by granulocyte colony-stimulating factor on left ventricular function and remodeling in patients with acute myocardial infarction versus old myocardial infarction: the MAGIC Cell-3-DES randomized, controlled trial.
        Circulation. 2006; 114: I145-I151
        • Bartunek J.
        • Wijns W.
        • Heyndrickx G.R.
        • et al.
        Timing of intracoronary bone-marrow-derived stem cell transplantation after ST-elevation myocardial infarction.
        Nat Clin Pract Cardiovasc Med. 2006; 3: S52-S56
        • Traverse J.H.
        • Henry T.D.
        • Vaughan D.E.
        • et al.
        Rationale and design for TIME: a phase II, randomized, double-blind, placebo-controlled pilot trial evaluating the safety and effect of timing of administration of bone marrow mononuclear cells after acute myocardial infarction.
        Am Heart J. 2009; 158: 356-363
        • Hou D.
        • Youssef E.A.
        • Brinton T.J.
        • et al.
        Radiolabeled cell distribution after intramyocardial, intracoronary, and interstitial retrograde coronary venous delivery: implications for current clinical trials.
        Circulation. 2005; 112: I150-I156
        • Hofmann M.
        • Wollert K.C.
        • Meyer G.P.
        • et al.
        Monitoring of bone marrow cell homing into the infarcted human myocardium.
        Circulation. 2005; 111: 2198-2202
        • Kawamoto A.
        • Iwasaki H.
        • Kusano K.
        • et al.
        CD34-positive cells exhibit increased potency and safety for therapeutic neovascularization after myocardial infarction compared with total mononuclear cells.
        Circulation. 2006; 114: 2163-2169
        • Kawamoto A.
        • Tkebuchava T.
        • Yamaguchi J.
        • et al.
        Intramyocardial transplantation of autologous endothelial progenitor cells for therapeutic neovascularization of myocardial ischemia.
        Circulation. 2003; 107: 461-468
        • Huang P.P.
        • Li S.Z.
        • Han M.Z.
        • et al.
        Autologous transplantation of peripheral blood stem cells as an effective therapeutic approach for severe arteriosclerosis obliterans of lower extremities.
        Thromb Haemost. 2004; 91: 606-609
        • Peichev M.
        • Naiyer A.J.
        • Pereira D.
        • et al.
        Expression of VEGFR-2 and AC133 by circulating human CD34(+) cells identifies a population of functional endothelial precursors.
        Blood. 2000; 95: 952-958
        • Fukumoto Y.
        • Miyamoto T.
        • Okamura T.
        • et al.
        Angina pectoris occurring during granulocyte colony-stimulating factor-combined preparatory regimen for autologous peripheral blood stem cell transplantation in a patient with acute myelogenous leukaemia.
        Br J Haematol. 1997; 97: 666-668
        • Kawachi Y.
        • Watanabe A.
        • Uchida T.
        • Yoshizawa K.
        • Kurooka N.
        • Setsu K.
        Acute arterial thrombosis due to platelet aggregation in a patient receiving granulocyte colony-stimulating factor.
        Br J Haematol. 1996; 94: 413-416
        • Seeger F.H.
        • Tonn T.
        • Krzossok N.
        • Zeiher A.M.
        • Dimmeler S.
        Cell isolation procedures matter: a comparison of different isolation protocols of bone marrow mononuclear cells used for cell therapy in patients with acute myocardial infarction.
        Eur Heart J. 2007; 28: 766-772
        • Norgren L.
        • Hiatt W.R.
        • Dormandy J.A.
        • et al.
        Inter-society consensus for the management of peripheral arterial disease (TASC II).
        Eur J Vasc Endovasc Surg. 2007; 33 (S1e75)
        • Adam D.J.
        • Beard J.D.
        • Cleveland T.
        • et al.
        Bypass versus angioplasty in severe ischaemia of the leg (BASIL): multicentre, randomised controlled trial.
        Lancet. 2005; 366: 1925-1934
      1. Second European Consensus Document on chronic critical leg ischemia.
        Circulation. 1991; 84 (IV1e26)
        • Hirsch A.T.
        • Haskal Z.J.
        • Hertzer N.R.
        • et al.
        ACC/AHA 2005 Practice Guidelines for the management of patients with peripheral arterial disease (lower extremity, renal, mesenteric, and abdominal aortic).
        Circulation. 2006; 113: e463-e654
        • Landry G.J.
        Functional outcome of critical limb ischemia.
        J Vasc Surg. 2007; 45: A141-A148
        • Tateishi-Yuyama E.
        • Matsubara H.
        • Murohara T.
        • et al.
        Therapeutic angiogenesis for patients with limb ischemia by autologous transplantation of bone-marrow cells: a pilot study and a randomised controlled trial.
        Lancet. 2002; 360: 427-435
        • Huang P.P.
        • Yang X.F.
        • Li S.Z.
        • et al.
        Randomised comparison of G-CSF-mobilized peripheral blood mononuclear cells versus bone marrow-mononuclear cells for the treatment of patients with lower limb arteriosclerosis obliterans.
        Thromb Haemost. 2007; 98: 1335-1342
        • Higashi Y.
        • Kimura M.
        • Hara K.
        • et al.
        Autologous bone-marrow mononuclear cell implantation improves endothelium-dependent vasodilation in patients with limb ischemia.
        Circulation. 2004; 109: 1215-1218
        • Amann B.
        • Luedemann C.
        • Ratei R.
        • et al.
        Autologous bone marrow cell transplantation increases leg perfusion and reduces amputations in patients with advanced critical limb ischemia due to peripheral artery disease.
        Cell Transplant. 2009; 18: 371-380
        • Bartsch T.
        • Brehm M.
        • Zeus T.
        • et al.
        Transplantation of autologous mononuclear bone marrow stem cells in patients with peripheral arterial disease (the TAM-PAD study).
        Clin Res Cardiol. 2007; 96: 891-899
        • Gu Y.Q.
        • Zhang J.
        • Guo L.R.
        • et al.
        Transplantation of autologous bone marrow mononuclear cells for patients with lower limb ischemia.
        Chin Med J (Engl). 2008; 121: 963-967
        • Huang P.
        • Li S.
        • Han M.
        • et al.
        Autologous transplantation of granulocyte colonystimulating factor-mobilized peripheral blood mononuclear cells improves critical limb ischemia in diabetes.
        Diabetes Care. 2005; 28: 2155-2160
        • Kawamura A.
        • Horie T.
        • Tsuda I.
        • et al.
        Clinical study of therapeutic angiogenesis by autologous peripheral blood stem cell (PBSC) transplantation in 92 patients with critically ischemic limbs.
        J Artif Organs. 2006; 9 (226–3)
        • Burt R.K.
        • Testori A.
        • Oyama Y.
        • et al.
        Autologous peripheral blood CD133+ cell implantation for limb salvage in patients with critical limb ischemia.
        Bone Marrow Transplant. 2010; 45: 111-116
        • Van Huyen J.P.
        • Smadja D.M.
        • Bruneval P.
        • et al.
        Bone marrow-derived mononuclear cell therapy induces distal angiogenesis after local injection in critical leg ischemia.
        Mod Pathol. 2008; 21: 837-846
        • Chochola M.
        • Pytlík R.
        • Kobylka P.
        • et al.
        Autologous intra-arterial infusion of bone marrow mononuclear cells in patients with critical leg ischemia.
        Int Angiol. 2008; 27: 281-290
        • Van Tongeren R.B.
        • Hamming J.F.
        • Fibbe W.E.
        • et al.
        Intramuscular or combined intramuscular/intra-arterial administration of bone marrow mononuclear cells: a clinical trial in patients with advanced limb ischemia.
        J Cardiovasc Surg (Torino). 2008; 49: 51-58
        • Bergmann O.
        • Bhardwaj R.D.
        • Bernard S.
        • et al.
        Evidence for cardiomyocyte renewal in humans.
        Science. 2009; 324: 98-102