First-generation stem cells are comprised of unselected cell mixtures exemplified by unfractionated bone-marrow-derived mononuclear stem cells
Initial stem-cell trials have established safety and feasibility, but show limited efficacy in the context of cardiovascular disease
The main hurdles to achieving benefit from stem-cell therapy include poorly defined cell populations, quality control in cell processing, and limited efficiency in cell delivery
To improve the regenerative effect, investigators have focused on purified cell populations to eliminate nonregenerative cells
Next-generation cell therapy ushers a new era in regenerative medicine by targeting organ or disease before implantation
The interplay between the diseased heart and regenerative biotherapeutics is critical in achieving repair
The global impetus to identify curative therapies has been fuelled by the unmet needs of patients in the context of a growing heart failure pandemic. To date, regeneration trials in patients with cardiovascular disease have used stem-cell-based therapy in the period immediately after myocardial injury, in an attempt to halt progression towards ischaemic cardiomyopathy, or in the setting of congestive heart failure, to target the disease process and prevent organ decompensation. Worldwide, several thousand patients have now been treated using autologous cell-based therapy; the safety and feasibility of this approach has been established, pitfalls have been identified, and optimization procedures envisioned. Furthermore, the initiation of phase III trials to further validate the therapeutic value of cell-based regenerative medicine and address the barriers to successful clinical implementation has led to resurgence in the enthusiasm for such treatments among patients and health-care providers. In particular, poor definition of cell types used, diversity in cell-handling procedures, and functional variability intrinsic to autologously-derived cells have been identified as the main factors limiting adoption of cell-based therapies. In this Review, we summarize the experience obtained from trials of 'first-generation' cell-based therapy, and emphasize the advances in the purification and lineage specification of stem cells that have enabled the development of 'next-generation' stem-cell-based therapies targeting cardiovascular disease.
Subscribe to Journal
Get full journal access for 1 year
only $4.92 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Oskouei, B. N. et al. Increased potency of cardiac stem cells compared with bone marrow mesenchymal stem cells in cardiac repair. Stem Cells Transl. Med. 1, 116–124 (2012).
Clifford, D. M. et al. Stem cell treatment for acute myocardial infarction. Cochrane Database of Systematic Reviews, Issue 2. Art. No.: CD006536. http://dx.doi.org/10.1002/14651858.CD006536.pub3 (2012).
Ezekowitz, J. A. et al. Declining in-hospital mortality and increasing heart failure incidence in elderly patients with first myocardial infarction. J. Am. Coll. Cardiol. 53, 13–20 (2009).
Go, A. S. et al. Heart disease and stroke statistics—2013 update: a report from the American Heart Association. Circulation 127, e6–e245 (2013).
Rohde, L. E., Bertoldi, E. G., Goldraich, L. & Polanczyk, C. A. Cost-effectiveness of heart failure therapies. Nat. Rev. Cardiol. 10, 338–354 (2013).
Heidenreich, P. A. et al. Forecasting the future of cardiovascular disease in the United States: a policy statement from the American Heart Association. Circulation 123, 933–944 (2011).
Braunschweig, F., Cowie, M. R. & Auricchio, A. What are the costs of heart failure? Europace 13 (Suppl. 2), ii13–ii17 (2011).
Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. The SOLVD Investigators. N. Engl. J. Med. 325, 293–302 (1991).
Bristow, M. R., Feldman, A. M. & Saxon, L. A. Heart failure management using implantable devices for ventricular resynchronization: Comparison of Medical Therapy, Pacing, and Defibrillation in Chronic Heart Failure (COMPANION) trial. COMPANION Steering Committee and COMPANION Clinical Investigators. J. Card. Fail. 6, 276–285 (2000).
Domanski, M. J. et al. A comparative analysis of the results from 4 trials of beta-blocker therapy for heart failure: BEST, CIBIS-II, MERIT-HF, and COPERNICUS. J. Card. Fail. 9, 354–363 (2003).
Gheorghiade, M. & Pitt, B. Digitalis Investigation Group (DIG) trial: a stimulus for further research. Am. Heart J. 134, 3–12 (1997).
Bristow, M. R. et al. Cardiac-resynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure. N. Engl. J. Med. 350, 2140–2150 (2004).
Rose, E. A. et al. Long-term use of a left ventricular assist device for end-stage heart failure. N. Engl. J. Med. 345, 1435–1443 (2001).
Gerczuk, P. Z. & Kloner, R. A. An update on cardioprotection: a review of the latest adjunctive therapies to limit myocardial infarction size in clinical trials. J. Am. Coll. Cardiol. 59, 969–978 (2012).
Assmus, B. et al. Transplantation of Progenitor Cells and Regeneration Enhancement in Acute Myocardial Infarction (TOPCARE-AMI). Circulation 106, 3009–3017 (2002).
Janssens, S. et al. Autologous bone marrow-derived stem-cell transfer in patients with ST-segment elevation myocardial infarction: double-blind, randomised controlled trial. Lancet 367, 113–121 (2006).
Tendera, M. 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. 30, 1313–1321 (2009).
Schachinger, V. et al. Intracoronary bone marrow-derived progenitor cells in acute myocardial infarction. N. Engl. J. Med. 355, 1210–1221 (2006).
Wollert, K. C. et al. Intracoronary autologous bone-marrow cell transfer after myocardial infarction: the BOOST randomised controlled clinical trial. Lancet 364, 141–148 (2004).
Wollert, K. C. & Drexler, H. Cell therapy for the treatment of coronary heart disease: a critical appraisal. Nat. Rev. Cardiol. 7, 204–215 (2010).
Perin, E. C. et al. Transendocardial, autologous bone marrow cell transplantation for severe, chronic ischemic heart failure. Circulation 107, 2294–2302 (2003).
Rehman, J. Bone marrow tinctures for cardiovascular disease: lost in translation. Circulation 127, 1935–1937 (2013).
Strauer, B. E. & Steinhoff, G. 10 years of intracoronary and intramyocardial bone marrow stem cell therapy of the heart: from the methodological origin to clinical practice. J. Am. Coll. Cardiol. 58, 1095–1104 (2011).
Traverse, J. H. et al. Effect of the use and timing of bone marrow mononuclear cell delivery on left ventricular function after acute myocardial infarction: the TIME randomized trial. JAMA 308, 2380–2389 (2012).
Perin, E. C. 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 FOCUS-CCTRN trial. JAMA 307, 1717–1726 (2012).
Traverse, J. H. et al. Effect of intracoronary delivery of autologous bone marrow mononuclear cells 2 to 3 weeks following acute myocardial infarction on left ventricular function: the LateTIME randomized trial. JAMA 306, 2110–2119 (2011).
Fish, K. M. et al. AAV9.I-1c delivered via direct coronary infusion in a porcine model of heart failure improves contractility and mitigates adverse remodeling. Circ. Heart Fail. 6, 310–317 (2013).
Penn, M. S. & Mangi, A. A. Genetic enhancement of stem cell engraftment, survival, and efficacy. Circ. Res. 102, 1471–1482 (2008).
Atala, A. Engineering organs. Curr. Opin. Biotechnol. 20, 575–592 (2009).
Badylak, S. F., Weiss, D. J., Caplan, A. & Macchiarini, P. Engineered whole organs and complex tissues. Lancet 379, 943–952 (2012).
Behfar, A. et al. Guided cardiopoiesis enhances therapeutic benefit of bone marrow human mesenchymal stem cells in chronic myocardial infarction. J. Am. Coll. Cardiol. 56, 721–734 (2010).
Dietz, A. B., Padley, D. J. & Gastineau, D. A. Infrastructure development for human cell therapy translation. Clin. Pharmacol. Ther. 82, 320–324 (2007).
Orlic, D. et al. Bone marrow cells regenerate infarcted myocardium. Nature 410, 701–705 (2001).
Deb, A. et al. Bone marrow-derived cardiomyocytes are present in adult human heart: a study of gender-mismatched bone marrow transplantation patients. Circulation 107, 1247–1249 (2003).
Jackson, K. A. et al. Regeneration of ischemic cardiac muscle and vascular endothelium by adult stem cells. J. Clin. Invest. 107, 1395–1402 (2001).
Meyer, G. P. 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 113, 1287–1294 (2006).
Strauer, B. E. et al. Repair of infarcted myocardium by autologous intracoronary mononuclear bone marrow cell transplantation in humans. Circulation 106, 1913–1918 (2002).
Fernandez-Aviles, F. et al. Experimental and clinical regenerative capability of human bone marrow cells after myocardial infarction. Circ. Res. 95, 742–748 (2004).
Meyer, G. P. et al. Intracoronary bone marrow cell transfer after myocardial infarction: 5-year follow-up from the randomized-controlled BOOST trial. Eur. Heart J. 30, 2978–2984 (2009).
Assmus, B. et al. Clinical outcome 2 years after intracoronary administration of bone marrow-derived progenitor cells in acute myocardial infarction. Circ. Heart Fail. 3, 89–96 (2010).
Huikuri, H. V. 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. 29, 2723–2732 (2008).
Lunde, K. et al. Intracoronary injection of mononuclear bone marrow cells in acute myocardial infarction. N. Engl. J. Med. 355, 1199–1209 (2006).
Hirsch, A. et al. Intracoronary infusion of autologous mononuclear bone marrow cells or peripheral mononuclear blood cells after primary percutaneous coronary intervention: rationale and design of the HEBE trial—a prospective, multicenter, randomized trial. Am. Heart J. 152, 434–441 (2006).
Hirsch, A. 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. 32, 1736–1747 (2011).
Janssens, S. P. Cardiac bone marrow cell therapy: the proof of the pudding remains in the eating. Eur. Heart J. 32, 1697–1700 (2011).
Surder, D. et al. Cell-based therapy for myocardial repair in patients with acute myocardial infarction: rationale and study design of the SWiss multicenter Intracoronary Stem cells Study in Acute Myocardial Infarction (SWISS-AMI). Am. Heart J. 160, 58–64 (2010).
Menasche, P. et al. Autologous skeletal myoblast transplantation for severe postinfarction left ventricular dysfunction. J. Am. Coll. Cardiol. 41, 1078–1083 (2003).
Menasche, P. et al. The Myoblast Autologous Grafting in Ischemic Cardiomyopathy (MAGIC) trial: first randomized placebo-controlled study of myoblast transplantation. Circulation 117, 1189–1200 (2008).
Assmus, B. et al. Transcoronary transplantation of progenitor cells after myocardial infarction. N. Engl. J. Med. 355, 1222–1232 (2006).
Assmus, B. et al. Transcoronary transplantation of functionally competent BMCs is associated with a decrease in natriuretic peptide serum levels and improved survival of patients with chronic postinfarction heart failure: results of the TOPCARE-CHD Registry. Circ. Res. 100, 1234–1241 (2007).
Dimmeler, S., Burchfield, J. & Zeiher, A. M. Cell-based therapy of myocardial infarction. Arterioscler. Thromb. Vasc. Biol. 28, 208–216 (2008).
Huang, X. P. et al. Differentiation of allogeneic mesenchymal stem cells induces immunogenicity and limits their long-term benefits for myocardial repair. Circulation 122, 2419–2429 (2010).
Hare, J. M. 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 308, 2369–2379 (2012).
Egeland, T. & Brinchmann, J. E. The REPAIR-AMI and ASTAMI trials: cell isolation procedures. Eur. Heart J. 28, 2174–2175 (2007).
Seeger, F. H. et al. Heparin disrupts the CXCR4/SDF-1 axis and impairs the functional capacity of bone marrow-derived mononuclear cells used for cardiovascular repair. Circ. Res. 111, 854–862 (2012).
US National Library of Medicine. ClinicalTrials.gov [online], (2013).
Perin, E. C. & Willerson, J. T. CD34+ autologous human stem cells in treating refractory angina. Circ. Res. 109, 351–352 (2011).
Jiang, Y. et al. Pluripotency of mesenchymal stem cells derived from adult marrow. Nature 418, 41–49 (2002).
Ross, J. J. et al. Cytokine-induced differentiation of multipotent adult progenitor cells into functional smooth muscle cells. J. Clin. Invest. 116, 3139–3149 (2006).
Schwartz, R. E. et al. Multipotent adult progenitor cells from bone marrow differentiate into functional hepatocyte-like cells. J. Clin. Invest. 109, 1291–1302 (2002).
Mangi, A. A. et al. Mesenchymal stem cells modified with Akt prevent remodeling and restore performance of infarcted hearts. Nat. Med. 9, 1195–1201 (2003).
Marban, E. & Malliaras, K. Mixed results for bone marrow-derived cell therapy for ischemic heart disease. JAMA 308, 2405–2406 (2012).
Losordo, D. W. et al. Intramyocardial, autologous CD34+ cell therapy for refractory angina. Circ. Res. 109, 428–436 (2011).
Heldman, A. W. et al. Transendocardial Mesenchymal Stem Cells and Mononuclear Bone Marrow Cells for Ischemic Cardiomyopathy: the TAC-HFT randomized trial. JAMA 311, 62–73 (2014).
Perin, E. C. et al. First in man transendocardial injection of autologous adipose-derived stem cells in patients with non revascularizable ischemic myocardium (PRECISE) [abstract]. Circulation 122, A17966 (2010).
Houtgraaf, J. H. et al. First experience in humans using adipose tissue-derived regenerative cells in the treatment of patients with ST-segment elevation myocardial infarction. J. Am. Coll. Cardiol. 59, 539–540 (2012).
Ruifrok, W. P. et al. Estradiol-induced, endothelial progenitor cell-mediated neovascularization in male mice with hind-limb ischemia. Vasc. Med. 14, 29–36 (2009).
Lee, J. H., Lee, S. H., Yoo, S. Y., Asahara, T. & Kwon, S. M. CD34 hybrid cells promote endothelial colony-forming cell bioactivity and therapeutic potential for ischemic diseases. Arterioscler. Thromb. Vasc. Biol. 33, 1622–1634 (2013).
Losordo, D. W. et al. A randomized, controlled pilot study of autologous CD34+ cell therapy for critical limb ischemia. Circ. Cardiovasc. Interv. 5, 821–830 (2012).
van Ramshorst, J. et al. Intramyocardial bone marrow cell injection for chronic myocardial ischemia: a randomized controlled trial. JAMA 301, 1997–2004 (2009).
Losordo, D. W. et al. Intramyocardial transplantation of autologous CD34+ stem cells for intractable angina: a phase I/IIa double-blind, randomized controlled trial. Circulation 115, 3165–3172 (2007).
Vrtovec, B. et al. Comparison of transendocardial and intracoronary CD34+ cell transplantation in patients with nonischemic dilated cardiomyopathy. Circulation 128, S42–S49 (2013).
Bolli, R. et al. Cardiac stem cells in patients with ischaemic cardiomyopathy (SCIPIO): initial results of a randomised phase 1 trial. Lancet 378, 1847–1857 (2011).
Heusch, G. SCIPIO brings new momentum to cardiac cell therapy. Lancet 378, 1827–1828 (2011).
Urbanek, K. et al. Human cardiac stem cells. J. Mol. Cell. Cardiol. 38, 838–839 (2005).
Chugh, A. R. et al. Administration of cardiac stem cells in patients with ischemic cardiomyopathy: the SCIPIO trial: surgical aspects and interim analysis of myocardial function and viability by magnetic resonance. Circulation 126, S54–S64 (2012).
Makkar, R. R. et al. Intracoronary cardiosphere-derived cells for heart regeneration after myocardial infarction (CADUCEUS): a prospective, randomised phase 1 trial. Lancet 379, 895–904 (2012).
Siu, C. W. & Tse, H. F. Cardiac regeneration: messages from CADUCEUS. Lancet 379, 870–871 (2012).
Chimenti, I. et al. Relative roles of direct regeneration versus paracrine effects of human cardiosphere-derived cells transplanted into infarcted mice. Circ. Res. 106, 971–980 (2010).
Smith, R. R. et al. Regenerative potential of cardiosphere-derived cells expanded from percutaneous endomyocardial biopsy specimens. Circulation 115, 896–908 (2007).
Messina, E. et al. Isolation and expansion of adult cardiac stem cells from human and murine heart. Circ. Res. 95, 911–921 (2004).
Johnston, P. V. et al. Engraftment, differentiation, and functional benefits of autologous cardiosphere-derived cells in porcine ischemic cardiomyopathy. Circulation 120, 1075–1083 (2009).
Murry, C. E., Palpant, N. J. & Maclellan, W. R. Cardiopoietry in motion: primed mesenchymal stem cells for ischemic cardiomyopathy. J. Am. Coll. Cardiol. 61, 2339–2340 (2013).
US National Library of Medicine. ClinicalTrials.gov [online], (2012).
US National Library of Medicine. ClinicalTrials.gov [online], (2013).
Fujita, J. Report of the American Heart Association (AHA) Scientific Sessions 2012, Los Angeles. Circ. J. 77, 35–40 (2013).
Behfar, A. & Terzic, A. Derivation of a cardiopoietic population from human mesenchymal stem cells yields cardiac progeny. Nat. Clin. Pract. Cardiovasc. Med. 3 (Suppl. 1), S78–S82 (2006).
Bartunek, J. et al. Cardiopoietic stem cell therapy in heart failure: the C-CURE (Cardiopoietic stem Cell therapy in heart failURE) multicenter randomized trial with lineage-specified biologics. J. Am. Coll. Cardiol. 61, 2329–2338 (2013).
Kattman, S. J. et al. Stage-specific optimization of activin/nodal and BMP signaling promotes cardiac differentiation of mouse and human pluripotent stem cell lines. Cell Stem Cell 8, 228–240 (2011).
Mummery, C. et al. Differentiation of human embryonic stem cells to cardiomyocytes: role of coculture with visceral endoderm-like cells. Circulation 107, 2733–2740 (2003).
Behfar, A. et al. Cardiopoietic programming of embryonic stem cells for tumor-free heart repair. J. Exp. Med. 204, 405–420 (2007).
Behfar, A. et al. Stem cell differentiation requires a paracrine pathway in the heart. FASEB J. 16, 1558–1566 (2002).
Laflamme, M. A. et al. Cardiomyocytes derived from human embryonic stem cells in pro-survival factors enhance function of infarcted rat hearts. Nat. Biotechnol. 25, 1015–1024 (2007).
US National Library of Medicine. ClinicalTrials.gov [online], (2014).
Assmus, B. et al. Effect of shock wave-facilitated intracoronary cell therapy on LVEF in patients with chronic heart failure: the CELLWAVE randomized clinical trial. JAMA 309, 1622–1631 (2013).
Telukuntla, K. S., Suncion, V. Y., Schulman, I. H. & Hare, J. M. The advancing field of cell-based therapy: insights and lessons from clinical trials. J. Am. Heart Assoc. 2, e000338 (2013).
Ranganath, S. H., Levy, O., Inamdar, M. S. & Karp, J. M. Harnessing the mesenchymal stem cell secretome for the treatment of cardiovascular disease. Cell Stem Cell 10, 244–258 (2012).
Passier, R., van Laake, L. W. & Mummery, C. L. Stem-cell-based therapy and lessons from the heart. Nature 453, 322–329 (2008).
Ellison, G. M. et al. Endogenous cardiac stem cell activation by insulin-like growth factor-1/hepatocyte growth factor intracoronary injection fosters survival and regeneration of the infarcted pig heart. J. Am. Coll. Cardiol. 58, 977–986 (2011).
Linke, A. et al. Stem cells in the dog heart are self-renewing, clonogenic, and multipotent and regenerate infarcted myocardium, improving cardiac function. Proc. Natl Acad. Sci. USA 102, 8966–8971 (2005).
Beohar, N., Rapp, J., Pandya, S. & Losordo, D. W. Rebuilding the damaged heart: the potential of cytokines and growth factors in the treatment of ischemic heart disease. J. Am. Coll. Cardiol. 56, 1287–1297 (2010).
Ripa, R. S. et al. Stem cell mobilization induced by subcutaneous granulocyte-colony stimulating factor to improve cardiac regeneration after acute ST-elevation myocardial infarction: result of the double-blind, randomized, placebo-controlled stem cells in myocardial infarction (STEMMI) trial. Circulation 113, 1983–1992 (2006).
Henry, T. D. et al. The VIVA trial: vascular endothelial growth factor in Ischemia for vascular angiogenesis. Circulation 107, 1359–1365 (2003).
Gyöngyösi, M. et al. NOGA-guided analysis of regional myocardial perfusion abnormalities treated with intramyocardial injections of plasmid encoding vascular endothelial growth factor A-165 in patients with chronic myocardial ischemia: subanalysis of the EUROINJECT-ONE multicenter double-blind randomized study. Circulation 112 (9 Suppl.), I157–I165 (2005).
Gnecchi, M. et al. Evidence supporting paracrine hypothesis for Akt-modified mesenchymal stem cell-mediated cardiac protection and functional improvement. FASEB J. 20, 661–669 (2006).
Losordo, D. W. et al. Gene therapy for myocardial angiogenesis: initial clinical results with direct myocardial injection of phVEGF165 as sole therapy for myocardial ischemia. Circulation 98, 2800–2804 (1998).
Schumacher, B., Stegmann, T. & Pecher, P. The stimulation of neoangiogenesis in the ischemic human heart by the growth factor FGF: first clinical results. J. Cardiovasc. Surg. (Torino) 39, 783–789 (1998).
Gupta, R., Tongers, J. & Losordo, D. W. Human studies of angiogenic gene therapy. Circ. Res. 105, 724–736 (2009).
Engelmann, M. G. et al. Autologous bone marrow stem cell mobilization induced by granulocyte colony-stimulating factor after subacute ST-segment elevation myocardial infarction undergoing late revascularization: final results from the G-CSF-STEMI (Granulocyte Colony-Stimulating Factor ST-Segment Elevation Myocardial Infarction) trial. J. Am. Coll. Cardiol. 48, 1712–1721 (2006).
Zbinden, S., Zbinden, R., Meier, P., Windecker, S. & Seiler, C. Safety and efficacy of subcutaneous-only granulocyte-macrophage colony-stimulating factor for collateral growth promotion in patients with coronary artery disease. J. Am. Coll. Cardiol. 46, 1636–1642 (2005).
Penn, M. S. Importance of the SDF-1:CXCR4 axis in myocardial repair. Circ. Res. 104, 1133–1135 (2009).
Zhang, M. et al. SDF-1 expression by mesenchymal stem cells results in trophic support of cardiac myocytes after myocardial infarction. FASEB J. 21, 3197–3207 (2007).
Askari, A. T. et al. Effect of stromal-cell-derived factor 1 on stem-cell homing and tissue regeneration in ischaemic cardiomyopathy. Lancet 362, 697–703 (2003).
Penn, M. S. et al. An open-label dose escalation study to evaluate the safety of administration of nonviral stromal cell-derived factor-1 plasmid to treat symptomatic ischemic heart failure. Circ. Res. 112, 816–825 (2013).
Jujo, K. et al. CXC-chemokine receptor 4 antagonist AMD3100 promotes cardiac functional recovery after ischemia/reperfusion injury via endothelial nitric oxide synthase-dependent mechanism. Circulation 127, 63–73 (2013).
Singelyn, J. M. et al. Naturally derived myocardial matrix as an injectable scaffold for cardiac tissue engineering. Biomaterials 30, 5409–5416 (2009).
Singelyn, J. M. et al. Catheter-deliverable hydrogel derived from decellularized ventricular extracellular matrix increases endogenous cardiomyocytes and preserves cardiac function post-myocardial infarction. J. Am. Coll. Cardiol. 59, 751–763 (2012).
Ott, H. C. et al. Perfusion-decellularized matrix: using nature's platform to engineer a bioartificial heart. Nat. Med. 14, 213–221 (2008).
Zhang, J. et al. Extracellular matrix promotes highly efficient cardiac differentiation of human pluripotent stem cells: the matrix sandwich method. Circ. Res. 111, 1125–1136 (2012).
Dvir, T. et al. Nanowired three-dimensional cardiac patches. Nat. Nanotechnol. 6, 720–725 (2011).
Blin, G. et al. A purified population of multipotent cardiovascular progenitors derived from primate pluripotent stem cells engrafts in postmyocardial infarcted nonhuman primates. J. Clin. Invest. 120, 1125–1139 (2010).
Yu, J. et al. Induced pluripotent stem cell lines derived from human somatic cells. Science 318, 1917–1920 (2007).
Takahashi, K. et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131, 861–872 (2007).
Song, K. et al. Heart repair by reprogramming non-myocytes with cardiac transcription factors. Nature 485, 599–604 (2012).
Qian, L. et al. In vivo reprogramming of murine cardiac fibroblasts into induced cardiomyocytes. Nature 485, 593–598 (2012).
Ieda, M. et al. Direct reprogramming of fibroblasts into functional cardiomyocytes by defined factors. Cell 142, 375–386 (2010).
Fujita, J. & Sano, M. Treatment of the ventricular tachycardia with engraftment of pluripotent stem cells-derived cardiomyocytes. J. Mol. Cell. Cardiol. 53, 3–5 (2012).
Gepstein, L. et al. In vivo assessment of the electrophysiological integration and arrhythmogenic risk of myocardial cell transplantation strategies. Stem Cells 28, 2151–2161 (2010).
Hosoda, T. et al. Human cardiac stem cell differentiation is regulated by a mircrine mechanism. Circulation 123, 1287–1296 (2011).
Kajstura, J. et al. Cardiomyogenesis in the aging and failing human heart. Circulation 126, 1869–1881 (2012).
Bergmann, O. et al. Evidence for cardiomyocyte renewal in humans. Science 324, 98–102 (2009).
Delewi, R. et al. Impact of intracoronary bone marrow cell therapy on left ventricular function in the setting of ST-segment elevation myocardial infarction: a collaborative meta-analysis. Eur. Heart J. http://dx.doi.org/10.1093/eurheartj/eht372.
Jeevanantham, V. et al. Adult bone marrow cell therapy improves survival and induces long-term improvement in cardiac parameters: a systematic review and meta-analysis. Circulation 126, 551–568 (2012).
Behfar, A. et al. Optimized delivery system achieves enhanced endomyocardial stem cell retention. Circ. Cardiovasc. Interv. 6, 710–718 (2013).
Breitbach, M. et al. Potential risks of bone marrow cell transplantation into infarcted hearts. Blood 110, 1362–1369 (2007).
Makkar, R. et al. The CADUCEUS (CArdiosphere-Derived aUtologous stem CElls to reverse ventricUlar dySfunction) trial. Circulation 124, 2373 (2011).
Jungebluth, P. et al. Tracheobronchial transplantation with a stem-cell-seeded bioartificial nanocomposite: a proof-of-concept study. Lancet 378, 1997–2004 (2011).
Atala, A. Tissue engineering of human bladder. Br. Med. Bull. 97, 81–104 (2011).
Marini, J. C. & Forlino, A. Replenishing cartilage from endogenous stem cells. N. Engl. J. Med. 366, 2522–2524 (2012).
Andia, I. & Maffulli, N. Platelet-rich plasma for managing pain and inflammation in osteoarthritis. Nat. Rev. Rheumatol. 9, 721–730 (2013).
The authors declare no competing financial interests.
About this article
Cite this article
Behfar, A., Crespo-Diaz, R., Terzic, A. et al. Cell therapy for cardiac repair—lessons from clinical trials. Nat Rev Cardiol 11, 232–246 (2014). https://doi.org/10.1038/nrcardio.2014.9
The Potential Properties of Natural Compounds in Cardiac Stem Cell Activation: Their Role in Myocardial Regeneration
Injectable collagen scaffold promotes swine myocardial infarction recovery by long-term local retention of transplanted human umbilical cord mesenchymal stem cells
Science China Life Sciences (2021)
Journal of Cellular Physiology (2021)
miR-130a activates the VEGFR2/STAT3/HIF1α axis to potentiate the vasoregenerative capacity of endothelial colony-forming cells in hypoxia
Molecular Therapy - Nucleic Acids (2021)
Chemistry – An Asian Journal (2021)