Thromb Haemost 2010; 104(01): 6-12
DOI: 10.1160/TH09-05-0336
Theme Issue Article
Schattauer GmbH

Stem cells for myocardial repair

Chung-Wah Siu
1   Cardiology Division, Department of Medicine, Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong, China
2   Research Center of Heart, Brain, Hormone and Healthy Aging, University of Hong Kong, Hong Kong, China
,
Song-Yan Liao
1   Cardiology Division, Department of Medicine, Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong, China
,
Yuan Liu
1   Cardiology Division, Department of Medicine, Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong, China
,
Qizhou Lian
1   Cardiology Division, Department of Medicine, Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong, China
2   Research Center of Heart, Brain, Hormone and Healthy Aging, University of Hong Kong, Hong Kong, China
,
Hung-Fat Tse
1   Cardiology Division, Department of Medicine, Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong, China
2   Research Center of Heart, Brain, Hormone and Healthy Aging, University of Hong Kong, Hong Kong, China
› Author Affiliations
Financial support: This work was supported by grants the Hong Kong Research Grant Council General Research Fund (HKU 763306M, HKU 7747/08M to C.W.S. and H.F.T.) and the CC Wong Stem Cell Fund (to H.F.T.).
Further Information

Publication History

Received: 30 May 2009

Accepted after minor revision: 09 March 2009

Publication Date:
23 November 2017 (online)

Summary

There is a growing interest in the clinical application for stem cell as a novel therapy for treatment of acute myocardial infarction and chronic myocardial ischaemia. The initial premise is the transplanted exogenous stem cells can engraft and integrate with host myocardium for cardiac regeneration. However, recent experimental studies suggest that multiple mechanisms, including remodelling of extracellular matrix, enhancement of neovascularisation and recruitment of endogenous stem cells are more likely to contribute to the beneficial effects of stem cell therapy that direct trans-differentiation of stem cells into functional myocardium. Among different potential cell sources, bone marrow-derived cells and skeletal myoblasts have been tested in pilot clinical trials. Phase I/II randomised controlled clinical trials suggest that intracoronary or intramyocardial injection of bone marrow-derived cells may be safe and feasible strategies for treatment of acute myocardial infarction as well as chronic myocardial ischaemia. In addition, these studies show a modest, but significant improvement in left ventricular ejection fraction and clinical status of patients after cell transplantation. Nevertheless, most of these studies included a relatively small sample size (<200) and short duration of follow-up (<6 months), and the clinical efficacy of stem cell therapy need to be confirmed by future clinical trials. Furthermore, the optimal timing, cell types and mode of delivery need to be addressed, and strategies to improve cell survival and engraftment should also be developed to overcome the potential hurdles related to cell-based therapy.

 
  • References

  • 1 Lopez AD, Mathers CD, 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.
  • 2 Velagaleti RS, Pencina MJ, Murabito JM. et al Long-term trends in the incidence of heart failure after myocardial infarction. Circulation 2008; 118: 2057-2062.
  • 3 Menasche P. Stem cells for clinical use in cardiovascular medicine: current limitations and future perspectives. Thromb Haemost 2005; 94: 697-701.
  • 4 Quaini F, Urbanek K, Beltrami AP. et al Chimerism of the transplanted heart. N Engl J Med 2002; 346: 5-15.
  • 5 Tse HF, Siu CW, Zhu SG. et al Paracrine effects of direct intramyocardial implantation of bone marrow derived cells to enhance neovascularization in chronic ischaemic myocardium. Eur J Heart Fail 2007; 09: 747-753.
  • 6 Gnecchi M, Zhang Z, Ni A. et al Paracrine mechanisms in adult stem cell signaling and therapy. Circ Res 2008; 103: 1204-1219.
  • 7 Fedak PW. Paracrine effects of cell transplantation: modifying ventricular remodeling in the failing heart. Semin Thorac Cardiovasc Surg 2008; 20: 87-93.
  • 8 Balsam LB, Wagers AJ, Christensen JL. et al Haematopoietic stem cells adopt mature haematopoietic fates in ischaemic myocardium. Nature 2004; 428: 668-673.
  • 9 Murry CE, Soonpaa MH, Reinecke H. et al Haematopoietic stem cells do not transdifferentiate into cardiac myocytes in myocardial infarcts. Nature 2004; 428: 664-668.
  • 10 Yeghiazarians Y, Zhang Y, Prasad M. et al Injection of bone marrow cell extract into infarcted hearts results in functional improvement comparable to intact cell therapy. Mol Ther 2009; 17: 1250-1256.
  • 11 Menasche P, Hagege AA, Vilquin JT. et al Autologous skeletal myoblast transplantation for severe postinfarction left ventricular dysfunction. J Am Coll Cardiol 2003; 41: 1078-1083.
  • 12 Taylor DA, Atkins BZ, Hungspreugs P. et al Regenerating functional myocardium: improved performance after skeletal myoblast transplantation. Nat Med 1998; 04: 929-933.
  • 13 Roell W, Lewalter T, Sasse P. et al Engraftment of connexin 43-expressing cells prevents post-infarct arrhythmia. Nature 2007; 450: 819-824.
  • 14 Wadhwa M, Thorpe R. Haematopoietic growth factors and their therapeutic use. Thromb Haemost 2008; 99: 863-873.
  • 15 Huang PP, Yang XF, Li SZ. 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.
  • 16 Orlic D, Kajstura J, Chimenti S. et al Bone marrow cells regenerate infarcted myocardium. Nature 2001; 410: 701-705.
  • 17 Planat-Benard V, Silvestre JS, Cousin B. et al Plasticity of human adipose lineage cells toward endothelial cells: physiological and therapeutic perspectives. Circulation 2004; 109: 656-663.
  • 18 Miyahara Y, Nagaya N, Kataoka M. et al Monolayered mesenchymal stem cells repair scarred myocardium after myocardial infarction. Nat Med 2006; 12: 459-465.
  • 19 Ghodsizad A, Niehaus M, Kogler G. et al Transplanted human cord blood-de-rived unrestricted somatic stem cells improve left-ventricular function and pre-vent left-ventricular dilation and scar formation after acute myocardial infarction. Heart 2009; 95: 27-35.
  • 20 Bergmann O, Bhardwaj RD, Bernard S. et al Evidence for cardiomyocyte renewal in humans. Science 2009; 324: 98-102.
  • 21 Beltrami AP, Barlucchi L, Torella D. et al Adult cardiac stem cells are multipotent and support myocardial regeneration. Cell 2003; 114: 763-776.
  • 22 Kajstura J, Urbanek K, Rota M. et al Cardiac stem cells and myocardial disease. J Mol Cell Cardiol 2008; 45: 505-513.
  • 23 Goh G, Self T, Barbadillo Muñ, oz MD. et al Molecular and phenotypic analyses of human embryonic stem cell-derived cardiomyocytes: opportunities and challenges for clinical translation. Thromb Haemost 2005; 94: 728-737.
  • 24 Habib M, Caspi O, Gepstein L. Human embryonic stem cells for cardiomyogenesis. J Mol Cell Cardiol 2008; 45: 462-474.
  • 25 Emanueli C, Lako M, Stojkovic M. et al In search of the best candidate for regeneration of ischemic tissues: are embryonic/fetal stem cells more advantageous than adult counterparts?. Thromb Haemost 2005; 94: 738-749.
  • 26 Takahashi K, Tanabe K, Ohnuki M. et al Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 2007; 131: 861-872.
  • 27 Mauritz C, Schwanke K, Reppel M. et al Generation of functional murine cardiac myocytes from induced pluripotent stem cells. Circulation 2008; 118: 507-517.
  • 28 Okita K, Ichisaka T, Yamanaka S. Generation of germline-competent induced pluripotent stem cells. Nature 2007; 448: 313-317.
  • 29 Tse HF, Yiu KH, Lau CP. Bone marrow stem cell therapy for myocardial angiogenesis. Curr Vasc Pharmacol 2007; 05: 103-112.
  • 30 Suuronen EJ, Kuraitis D, Ruel M. Improving cell engraftment with tissue engineering. Semin Thorac Cardiovasc Surg 2008; 20: 110-114.
  • 31 Meyer GP, Wollert KC, 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.
  • 32 Wollert KC, Meyer GP, Lotz J, Ringes-Lichtenberg S. et al Intracoronary autologous bone-marrow cell transfer after myocardial infarction: the BOOST randomised controlled clinical trial. Lancet 2004; 364: 141-148.
  • 33 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, randomised controlled trial. Lancet 2006; 367: 113-121.
  • 34 Lunde K, Solheim S, Aakhus S. et al Intracoronary injection of mononuclear bone marrow cells in acute myocardial infarction. N Engl J Med 2006; 355: 1199-1209.
  • 35 Kang HJ, Lee HY, Na SH. 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: I145-151.
  • 36 Schachinger V, Erbs S, Elsasser A. et al Intracoronary bone marrow-derived progenitor cells in acute myocardial infarction. N Engl J Med 2006; 355: 1210-1221.
  • 37 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 (975) e979-915.
  • 38 Tendera M, Wojakowski W, Ruzyllo W. et al for the REGENT Investigators Intracoronary infusion of bone marrow-derived selected CD34+CXCR4+ cells and non-selected mononuclear cells in patients with acute STEMI and reduced left ventricular ejection fraction: results of randomized, multicentre Myocardial Regeneration by Intracoronary Infusion of Selected Population of Stem Cells in Acute Myocardial Infarction (REGENT) Trial. Eur Heart J 2009; 30: 1313-1321.
  • 39 Huikuri HV, Kervinen K, Niemela M. et al Effects of intracoronary injection of mononuclear bone marrow cells on left ventricular function, arrhythmia risk profile, and restenosis after thrombolytic therapy of acute myocardial infarction. Eur Heart J 2009; 29: 2723-2732.
  • 40 Abdel-Latif A, Bolli R, Tleyjeh IM. et al Adult bone marrow-derived cells for cardiac repair: a systematic review and meta-analysis. Arch Intern Med 2007; 167: 989-997.
  • 41 Lipinski MJ, Biondi-Zoccai GG, 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.
  • 42 Kang S, Yang YJ, Li CJ. et al Effects of intracoronary autologous bone marrow cells on left ventricular function in acute myocardial infarction: a systematic review and meta-analysis for randomized controlled trials. Coron Artery Dis 2008; 19: 327-335.
  • 43 Martin-Rendon E, Brunskill SJ, Hyde CJ. et al Autologous bone marrow stem cells to treat acute myocardial infarction: a systematic review. Eur Heart J 2008; 29: 1807-1818.
  • 44 Reffelmann T, Konemann S, Kloner RA. Promise of blood- and bone marrow-derived stem cell transplantation for functional cardiac repair: putting it in perspective with existing therapy. J Am Coll Cardiol 2009; 53: 305-308.
  • 45 Tse HF, Kwong YL, Chan JK, Lo G, Ho CL, Lau CP. Angiogenesis in ischaemic myocardium by intramyocardial autologous bone marrow mononuclear cell implantation. Lancet 2003; 361: 47-49.
  • 46 Losordo DW, Schatz RA, White CJ. 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.
  • 47 Tse HF, Thambar S, Kwong YL. 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.
  • 48 van Ramshorst J, Bax JJ, Beeres SL. et al Intramyocardial bone marrow cell injection for chronic myocardial ischemia: a randomized controlled trial. J Am Med Assoc 2009; 301: 1997-2004.
  • 49 Assmus B, Honold J, Schachinger V. et al Transcoronary transplantation of progenitor cells after myocardial infarction. N Engl J Med 2006; 355: 1222-1232.
  • 50 Menasché P, Alfieri O, Janssens S. et al The Myoblast Autologous Grafting in Ischemic Cardiomyopathy (MAGIC) trial: first randomized placebo-controlled study of myoblast transplantation. Circulation 2008; 117: 1189-1200.
  • 51 Egan CG, Caporali F, Huqi AF. et al Reduced levels of putative endothelial progenitor and CXCR4+ cells in coronary artery disease: Kinetics following percutaneous coronary intervention and asoociation with clinical characteristics. Thromb Haemost 2009; 101: 1138-1146.
  • 52 Seeger FH, Tonn T, Krzossok N. et al 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.
  • 53 Korf-Klingebiel M, Kempf T, Sauer T. et al Bone marrow cells are a rich source of growth factors and cytokines: implications for cell therapy trials after myocardial infarction. Eur Heart J 2008; 29: 2851-2858.
  • 54 Ii M, Nishimura H, Iwakura A, Wecker A. et al Endothelial progenitor cells are rapidly recruited to myocardium and mediate protective effect of ischemic pre-conditioning via �imported" nitric oxide synthase activity. Circulation 2005; 111: 1114-1120.
  • 55 Pons J, Huang Y, Arakawa-Hoyt J. et al VEGF improves survival of mesenchymal stem cells in infarcted hearts. Biochem Biophys Res Commun 2008; 376: 419-422.
  • 56 van der Bogt KE, Sheikh AY, Schrepfer S. et al Comparison of different adult stem cell types for treatment of myocardial ischemia. Circulation 2008; 118: S121-129.
  • 57 Elmadbouh I, Haider H, Jiang S. et al Ex vivo delivered stromal cell-derived factor-1alpha promotes stem cell homing and induces angiomyogenesis in the infarcted myocardium. J Mol Cell Cardiol 2007; 42: 792-803.