Stem cells in clinical practice for cardiovascular diseases
More details
Hide details
Department of Neurology and Neurosurgery, Faculty of Medical Sciences, University of Warmia and Mazury in Olsztyn, Poland
Laboratory of Regenerative Medicine, Faculty of Medical Sciences, University of Warmia and Mazury in Olsztyn, Poland
Department of Pathophysiology, Faculty of Medical Sciences, University of Warmia and Mazury in Olsztyn, Poland
Submission date: 2015-02-17
Acceptance date: 2015-09-21
Online publication date: 2015-12-19
Publication date: 2020-03-23
Corresponding author
Katarzyna Jezierska-Woźniak   

Warszawska 30, 10-082 Olsztyn, Poland. Tel.: +48 0895245338.
Pol. Ann. Med. 2016;23(1):49-56
According to a World Health Organization (WHO) report, 17.3 million people died from cardiovascular diseases (CVDs) in 2008, representing 30% of all global deaths, and almost 23.6 million people will die from CVDs by 2030. CVDs remain the predominant cause of mortality worldwide.

In this review, the authors discuss the current strategies and therapies targeting stem cells in CVDs.

Material and methods:
In this paper we present an overview of stem cell therapy for CVD and discuss the challenges these three areas present for maximum optimization of the efficacy of stem cell therapy for heart disease, and new strategies in progress.

Various kinds of therapeutic methods have been studied to improve prognosis in cardiovascular diseases. Stem cells comprise an enormous opportunity to rebuild damaged tissues. Most of the application and clinical trials involve the various types of stem cells derived mainly from bone marrow and others sources of mesenchymal stem cells. Early data from these trials have produced mixed results often showing minor or transitory improvements.

The divergences are attributed to differences in cell preparations, the large number of stem cell types under investigation in different clinical settings, timing, methods of cell administration and characteristics of patients.

None declared.
WHO. Cardiovascular Diseases. 2015. cardiovascular_diseases/en Accessed 10.02.15.
Hoover-Plow J, Gong Y. Challenges for heart disease stem cell therapy. Vasc Health Risk Manage. 2012;8:99–113.
Sanz-Ruiz R, Gutiérrez Ibañes E, Arranz AV, Fernández Santos ME, Fernández PL, Fernández-Avilés F. Phases I–III clinical trials using adult stem cells. Stem Cells Int. 2010;4:579142.
Mouquet F, Pfister O, Jain M, et al. Restoration of cardiac progenitor cells after myocardial infarction by selfproliferation and selective homing of bone marrow-derived stem cells. Circ Res. 2005;97:1090–1092.
Fazel S, Cimini M, Chen L, et al. Cardioprotective c-kit1 cells are from the bone marrow and regulate the myocardial balance of angiogenic cytokines. J Clin Invest. 2006;116:1865–1877.
Orlic D, Kajstura J, Chimenti S, et al. Bone marrow cells regenerate infarcted myocardium. Nature. 2001;410:701–705.
Krause DS, Theise ND, Collector MI, et al. Multi-organ, multilineage engraftment by a single bone marrow-derived stem cell. Cell. 2001;105:369–377.
Mezey E, Chandross KJ, Harta G, Maki RA, McKercher SR. Turning blood into brain: cells bearing neuronal antigens generated in vivo from bone marrow. Science. 2000;290:1779–1782.
Uemura R, Xu M, Ahmad N, Ashraf M. Bone marrow stem cells prevent left ventricular remodeling of ischemic heart through paracrine signaling. Circ Res. 2006;98:1414–1421.
Jackson KA, Majka SM, Wang H, et al. Regeneration of ischemic cardiac muscle and vascular endothelium by adult stem cells. J Clin Invest. 2001;107:1395–1402.
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.
Dai W, Hale SL, Martin BJ, et al. Allogeneic mesenchymal stem cell transplantation in postinfarcted rat myocardium: short- and long-term effects. Circulation. 2005;112:214–223.
Shake JG, Gruber PJ, Baumgartner WA, et al. Mesenchymal stem cell implantation in a swine myocardial infarct model: engraftment and functional effects. Ann Thorac Surg. 2002;73:1919–1925 [discussion 1926].
Strauer BE, Brehm M, Zeus T, et al. Intracoronary, human autologous stem cell transplantation for myocardial regeneration following myocardial infarction. Dtsch Med Wochenschr. 2001;126:932–938.
Meyer GP, Wollert KC, Lotz J. 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.
Abdel-Latif A, Bolli R, Tleyjeh IM, et al. Adult bone marrowderived cells for cardiac repair: a systematic review and meta-analysis. Arch Intern Med. 2007;167:989–997.
Schächinger V, Erbs S, Elsässer A, et al. Improved clinical outcome after intracoronary administration of bonemarrow-derived progenitor cells in acute myocardial infarction: final 1-year results of the REPAIR-AMI trial. Eur Heart J. 2006;27:2775–2783.
Huikuri HV, Kervinen K, Niemelä 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. 2008;29:2723–2732.
Tendera M, Wojakowski W, Ruzyłło W, et al. 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.
Srimahachota S, Boonyaratavej S, Rerkpattanapipat P, et al. Feasibility and safety of intra-coronary bone marrow mononuclear cell transplantation in ST elevation myocardial infarction patients. J Med Assoc Thai. 2009 Dec;92:1591–1596.
Beitnes JO, Gjesdal O, 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.
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.
Hirsch A, Nijveldt R, van der Vleuten PA, et al. Intracoronary infusion of mononuclear cells from bone marrow or peripheral blood compared with standard therapy in patients after acute myocardial infarction treated by primary percutaneous coronary intervention: results of the randomized controlled HEBE trial. Eur Heart J. 2011;32:1736–1747.
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.
Van Ramshorst J, Bax JJ, Beeres SL, et al. Intramyocardial bone marrow cell injection for chronic myocardial ischemia: a randomized controlled trial. JAMA. 2009;301:1997–2004.
Losordo DW, Schatz RA, White CJ, et al. Intramyocardial transplantation of autologous CD34+ stem cells for intractable angina: a phase 1/IIa double blind, randomized controlled trial. Circulation. 2007;115:3165–3172.
Penn MS, Ellis S, Gandhi S, et al. Adventitial delivery of an allogeneic bone marrow-derived adherent stem cell in acute myocardial infarction: phase I clinical study. Circ Res. 2012;110:304–311.
Zimmet H, Porapakkham P, Porapakkham P, et al. Short- and long-term outcomes of intracoronary and endogenously mobilized bone marrow stem cells in the treatment of STsegment elevation myocardial infarction: a meta-analysis of randomized control trials. Eur J Heart Fail. 2012;14:91–105.
Mohsin S, Siddiqi S, Collins B, Sussman MA. Empowering adult stem cells for myocardial regeneration. Circ Res. 2011;109:1415–1428.
Jakob P, Landmesser U. Role of microRNAs in stem/progenitor cells and cardiovascular repair. Cardiovasc Res. 2012;93:614–622.
Xu M, Wani M, Dai YS, et al. Differentiation of bone marrow stromal cells into the cardiac phenotype requires intercellular communication with myocytes. Circulation. 2004;110:2658–2665.
Pittenger MF, Mackay AM, Beck SC, et al. Multilineage potential of adult human mesenchymal stem cells. Science. 1999;284:143–147.
Yang YJ, Qian HY, Huang J, et al. Combined therapy with simvastatin and bone marrow-derived mesenchymal stem cells increases benefits in infarcted swine hearts. Arterioscle Thromb Vasc Biol. 2009;29:2076–2082.
Dixon JA, Gorman RC, Stroud RE, et al. Mesenchymal cell transplantation and myocardial remodeling after myocardial infarction. Circulation. 2009;120:S220–S229.
Halkos ME, Zhao ZQ, Kerendi F, et al. Intravenous infusion of mesenchymal stem cells enhances regional perfusion and improves ventricular function in a porcine model of myocardial infarction. Basic Res Cardiol. 2008;103:525–536.
Gnecchi M, Zhang Z, Ni A, Dzau VJ. Paracrine mechanisms in adult stem cell signaling and therapy. Circ Res. 2008;103:1204–1219.
Chen SL, Fang WW, Ye F, et al. Effect on left ventricular function of intracoronary transplantation of autologous bone marrow mesenchymal stem cell in patients with acute myocardial infarction. Am J Cardiol. 2004;94:92–95.
Hare JM, Traverse JH, Henry TD, et al. A randomized, doubleblind, placebo-controlled, dose-escalation study of intravenous adult human mesenchymal stem cells (prochymal) after acute myocardial infarction. J Am Coll Cardiol. 2009;54:2277–2286.
Williams AR, Trachtenberg B, Velazquez DL, et al. Intramyocardial stem cell injection in patients with ischemic cardiomyopathy: functional recovery and reverse remodeling. Circ Res. 2011;108:792–796.
Behfar A, Yamada S, Crespo-Diaz R, et al. Guided cardiopoiesis enhances therapeutic benefit of bone marrow human mesenchymal stem cells in chronic myocardial infarction. J Am Coll Cardiol. 2010;56:721–734.
Hare JM, Fishman JE, Gerstenblith G, et al. Comparison of allogeneic vs. autologous bone marrow-derived mesenchymal stem cells delivered by transendocardial injection in patients with ischemic cardiomyopathy: the POSEIDON randomized trial. JAMA. 2012;308:2369–2379.
Mazhari R, Hare JM. Mechanisms of action of mesenchymal stem cells in cardiac repair: potential influences on the cardiac stem cell niche. Nat Clin Pract Cardiovasc Med. 2007;4(suppl 1):S21–S26.
Hierlihy AM, Seale P, Lobe CG, Rudnicki MA, Megeney LA. The post-natal heart contains a myocardial stem cell population. FEBS Lett. 2002;530:239–243.
Pfister O, Mouquet F, Jain M, et al. CD31 – but not CD311 cardiac side population cells exhibit functional cardiomyogenic differentiation. Circ Res. 2005;97:52–61.
Ellison GM, Torella D, Karakikes I, Nadal-Ginard B. Myocyte death and renewal: modern concepts of cardiac cellular homeostasis. Nat Clin Pract Cardiovasc Med. 2007;4:S52–S59.
Kajstura J, Urbanek K, Rota M, et al. Cardiac stem cells and myocardial disease. J Mol Cell Cardiol. 2008;45:505–513.
Beltrami AP, Barlucchi L, Torella D, et al. Adult cardiac stem cells are multipotent and support myocardial regeneration. Cell. 2003;114:763–776.
Messina E, De Angelis L, Frati G, et al. Isolation and expansion of adult cardiac stem cells from human and murine heart. Circ Res. 2004;95:911–921.
Barile L, Messina E, Giacomello A, Marbán E. Endogenous cardiac stem cells. Prog Cardiovasc Dis. 2007;50:31–48.
Hosoda T, D'Amario D, Cabral-Da-Silva MC, et al. Clonality of mouse and human cardiomyogenesis in vivo. Proc Natl Acad Sci U S A. 2009;106:17169–17174.
Soonpaa MH, Field LJ. Assessment of cardiomyocyte DNA synthesis in normal and injured adult mouse hearts. Am J Physiol Heart Circ Physiol. 1997;272:H220–H226.
Bergmann O, Bhardwaj RD, Bernard S. Evidence for cardiomyocyte renewal in humans. Science. 2009;324:98–102.
Walsh S, Pontén A, Fleischmann BK, Jovinge S. Cardiomyocyte cell cycle control and growth estimation in vivo—an analysis based on cardiomyocyte nuclei. Cardiovasc Res. 2010;86:365–373.
Senyo SE, Steinhauser ML, Pizzimenti CL, et al. Mammalian heart renewal by pre-existing cardiomyocytes. Nature. 2013;493:433–436.
Linke A, Müller P, Nurzynska D, et al. Stem cells in the dog heart are self-renewing, clonogenic, and multipotent and regenerate infracted myocardium, improving cardiac function. Proc Natl Acad Sci U S A. 2005;102:8966–8971.
Ma Z, Yang H, Liu H, et al. Mesenchymal stem cell–cardiomyocyte interactions under defined contact modes on laser-patterned biochips. PLOS ONE. 2013;8:56554.
Konincky R, Daniëls A, Windmolders S, et al. Mesenchymal stem cells or cardiac progenitors for cardiac repair? A comparative study. Cell Mol Life Sci. 2011;68:2141–2156.
Wollert KC, Drexler H. Cell therapy for the treatment of coronary heart disease: a critical appraisal. Nat Rev Cardiol. 2010;7:204–215.
Simpson DL, Mishra R, Sharma S, Goh SK, Deshmukh S, Kaushal S. A strong regenerative ability of cardiac stem cells derived from neonatal hearts. Circulation. 2012;126(11 suppl 1):S46–S53.
Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell. 2006;126:663–676.
Okita K, Ichisaka T, Yamanaka S. Generation of germline competent induced pluripotent stem cells. Nature. 2007;448:313–317.
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.
Kawamura M, Miyagawa S, Miki K, et al. Feasibility, safety, and therapeutic efficacy of human induced pluripotent stem cell derived cardiomyocyte sheets in a porcine ischemic cardiomyopathy model. Circulation. 2012;126:S29–S37.
Ieda M, Fu JD, Delgado-Olguin P, et al. Direct reprogramming of fibroblasts into functional cardiomyocytes by defined factors. Cell. 2010;142:375–386.
Terrenoire C, Wang K, Tung KW, et al. Induced pluripotent stem cells used to reveal drug actions in a long QT syndrome family with complex genetics. J Gen Physiol. 2013;141:61–72.
Lee P, Klos M, Bollensdorff C, et al. Simultaneous voltage and calcium mapping of genetically purified human induced pluripotent stem cell-derived cardiac myocyte monolayers. Circ Res. 2012;110:1556–1563.
Randomized Clinical Trial of Adipose-Derived Stem Cells in the Treatment of Pts With ST-elevation Myocardial Infarction. 2015. Accessed 15.02.15.
Houtgraaf JH, den Dekker WK, van Dalen BM, et al. First experience in humans using adipose tissue-derived regenerative cells in the treatment of patients with STsegment elevation myocardial infarction. J Am Coll Cardiol. 2012;59:539–540.
Ince M, Petzsch M, Kleine HD, et al. Preservation from left ventricular remodeling by front-integrated revascularization and stem cell liberation in evolving acute myocardial infarction by use of granulocyte-colony-stimulating factor (FIRSTLINE-AMI). Circulation. 2005;112:3097–3106.
Leone AM, Galiuto L, Garramone B, et al. Usefulness of granulocyte colony-stimulating factor in patients with a large anterior wall acute myocardial infarction to prevent left ventricular remodeling (the Rigenera study). Am J Cardiol. 2007;100:397–403.
Takano H, Hasegawa H, Kuwabara Y, et al. Feasibility and safety of granulocyte colony-stimulating factor treatment in patients with acute myocardial infarction. Int J Cardiol. 2007;122:41–47.
Kang HJ, Kim HS, Zhang SY, et al. Effects of intracoronary infusion of peripheral blood stem-cells mobilized 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.
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–I151.
Menasch'e 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.
Dib N, Michler RE, Pagani FD, et al. Safety and feasibility of autologous myoblast transplantation in patients with ischemic cardiomyopathy: four-year follow-up. Circulation. 2005;112:1748–1755.
Bach I. The LIM domain: regulation by association. Mech Dev. 2000;91:5–17.
Witzel HR, Jungblut B, Choe CP, Crump JG, Braun T, Dobreva G. The LIM protein Ajuba restricts the second heart field progenitor pool by regulating Isl1 activity. Dev Cell. 2012;23:58–70.
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.
Roncalli J, Mouquet F, Piot C, et al. Intracoronary autologous mononucleated bone marrow cell infusion for acute myocardial infarction: results of the randomized multicenter BONAMI trial. Eur Heart J. 2011;32:1748–1757.
Perin EC, Willerson JT, Pepine CJ, et al. Effect of transendocardial delivery of autologous bone marrow mononuclear cells on functional capacity, left ventricular function, and perfusion in chronic heart failure: the FOCUSCCTRN trial. JAMA. 2012;307:1717–1726.
Hodgetts SI, Beilharz MW, Scalzo AA, Grounds MD. Why do cultured transplanted myoblasts die in vivo? DNA quantification shows enhanced survival of donor male myoblasts in host mice depleted of CD4+ and CD8+ cells or NKl, 1+ cells. Cell Transplant. 2000;9:489–502.
Tang YL, Tang Y, Zhang YC, Qian K, Shen L, Phillips MI. Improved graft mesenchymal stem cell survival in ischemic heart with a hypoxia-regulated heme oxygenase-1 vector. J Am Coll Cardiol. 2005;46:1339–1350.
van der Spoel TI, Jansen of Lorkeers SJ, Agostoni P, et al. Human relevance of pre-clinical studies in stem cell therapy: systematic review and meta-analysis of large animal models of ischaemic heart disease. Cardiovasc Res. 2011;91:649–658.
Ip JE, Wu Y, Huang J, Zhang L, Pratt RE, Dzau VJ. Mesenchymal stem cells use integrin b1 not CXC chemokine receptor 4 for myocardial migration and engraftment. Mol Biol Cell. 2007;18:2873–2882.
Borg TK, Markwald R. Periostin: more than just an adhesion molecule. Circ Res. 2007;101:230–231.
Xiang G, Schuster MD, Seki T, Witkowski P, Eshghi S, Itescu S. Down regulated expression of plasminogen activator inhibitor-1 augments myocardial neovascularization and reduces cardiomyocyte apoptosis after acute myocardial infarction. Am Coll Cardiol. 2005;46:S336–S341.
Shimazaki M, Nakamura K, Kii I. Periostin is essential for cardiac healing after acute myocardial infarction. J Exp Med. 2008;205:295–303.
Wu JC, Abraham MR, Kraitchman DL. Current perspectives on imaging cardiac stem cell therapy. J Nucl Med. 2010;51(suppl 1):128S–136S.
Hofmann M, Wollert KC, Meyer GP, et al. Monitoring of bone marrow cell homing into the infarcted human myocardium. Circulation. 2005;111:2198–2202.
Lyon A, Harding S. The potential of cardiac stem cell therapy for heart failure. Curr Opin Pharmacol. 2007;164–170.
Williams AR, Hatzistergos KE, Addicott B, et al. Enhanced effect of combining human cardiac stem cells and bone marrow mesenchymal stem cells to reduce infarct size and to restore cardiac function after myocardial infarction. Circulation. 2013;127:213–223.
Journals System - logo
Scroll to top