Thorac Cardiovasc Surg 2018; 66(01): 042-052
DOI: 10.1055/s-0037-1608835
Review Article
Georg Thieme Verlag KG Stuttgart · New York

Regenerative Medicine/Cardiac Cell Therapy: Adult/Somatic Progenitor Cells

Timo Z. Nazari-Shafti
1   Berlin Brandenburg Center for Regenerative Therapies, Berlin, Germany
2   DZHK (German Centre for Cardiovascular Research), Partner Site, Berlin, Germany
3   Deutsches Herzzentrum Berlin, Berlin, Germany
4   Berlin Institute of Health, Berlin, Germany
,
Jörg Kempfert
2   DZHK (German Centre for Cardiovascular Research), Partner Site, Berlin, Germany
,
Volkmar Falk
2   DZHK (German Centre for Cardiovascular Research), Partner Site, Berlin, Germany
3   Deutsches Herzzentrum Berlin, Berlin, Germany
,
Wilhelm Röll
5   Klinik für Herzchirurgie, Universitätsklinikum Bonn, Bonn, Germany
,
Christof Stamm
1   Berlin Brandenburg Center for Regenerative Therapies, Berlin, Germany
2   DZHK (German Centre for Cardiovascular Research), Partner Site, Berlin, Germany
3   Deutsches Herzzentrum Berlin, Berlin, Germany
› Institutsangaben
Weitere Informationen

Publikationsverlauf

31. Mai 2017

12. Oktober 2017

Publikationsdatum:
28. Dezember 2017 (online)

Abstract

Preclinical data suggested that somatic stem or progenitor cells derived induce and/or support endogenous repair mechanisms of the myocardium. Such cell populations were clearly shown to promote neovascularization in postischemic tissue, and some evidence also indicated transdifferentiation into cardiomyocytes. In the clinical setting, however, many attempts to regenerate damaged myocardium with a variety of autologous and allogeneic somatic progenitors have failed to generate the expected therapeutic efficacy. Currently, efforts are being made to select specific cellular subpopulations, modify somatic cells to augment their regenerative capacity, improve delivery methods, and develop markers selection of potentially responding patients. Cardiac surgical groups have pioneered and continue to advance the field of cellular therapies. While the initial excitement has subsided, the field has evolved into one of the pillars of surgical research and benefits from novel methods such as cellular reprogramming, genetic modification, and pluripotent stem cell technology. This review highlights developments and controversies in somatic cardiac cell therapy and provides a comprehensive overview of completed and ongoing clinical trials.

 
  • References

  • 1 Koh GY, Klug MG, Soonpaa MH, Field LJ. Differentiation and long-term survival of C2C12 myoblast grafts in heart. J Clin Invest 1993; 92 (03) 1548-1554
  • 2 Taylor DA, Atkins BZ, Hungspreugs P. , et al. Regenerating functional myocardium: improved performance after skeletal myoblast transplantation. Nat Med 1998; 4 (08) 929-933
  • 3 Kocher AA, Schuster MD, Szabolcs MJ. , 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 (04) 430-436
  • 4 Orlic D, Kajstura J, Chimenti S. , et al. Bone marrow cells regenerate infarcted myocardium. Nature 2001; 410 (6829): 701-705
  • 5 Strauer BE, Brehm M, Zeus T. , et al. Intracoronary, human autologous stem cell transplantation for myocardial regeneration following myocardial infarction [in German]. Dtsch Med Wochenschr 2001; 126 (34-35): 932-938
  • 6 Kalil RA, Ott D, Sant'Anna R. , et al. Autologous transplantation of bone marrow mononuclear stem cells by mini-thoracotomy in dilated cardiomyopathy: technique and early results. Sao Paulo Med J 2008; 126 (02) 75-81
  • 7 Fisher SA, Doree C, Mathur A, Martin-Rendon E. Meta-analysis of cell therapy trials for patients with heart failure. Circ Res 2015; 116 (08) 1361-1377
  • 8 Nowbar AN, Mielewczik M, Karavassilis M. , et al; DAMASCENE writing group. Discrepancies in autologous bone marrow stem cell trials and enhancement of ejection fraction (DAMASCENE): weighted regression and meta-analysis. BMJ 2014; 348 (7109): g2688
  • 9 Moyé L. DAMASCENE and meta-ecological research: a bridge too far. Circ Res 2014; 115 (05) 484-487
  • 10 Veltman CE, Soliman OII, Geleijnse ML. , et al. Four-year follow-up of treatment with intramyocardial skeletal myoblasts injection in patients with ischaemic cardiomyopathy. Eur Heart J 2008; 29 (11) 1386-1396
  • 11 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 (09) 1189-1200
  • 12 Leobon B, Garcin I, Menasche P, Vilquin J-T, Audinat E, Charpak S. Myoblasts transplanted into rat infarcted myocardium are functionally isolated from their host. Proc Natl Acad Sci U S A 2003; 100 (13) 7808-7811
  • 13 Roell W, Lewalter T, Sasse P. , et al. Engraftment of connexin 43-expressing cells prevents post-infarct arrhythmia. Nature 2007; 450 (7171): 819-824
  • 14 Uchinaka A, Tasaka K, Mizuno Y. , et al. Laminin α2-secreting fibroblasts enhance the therapeutic effect of skeletal myoblast sheets. Eur J Cardiothorac Surg 2017; 51 (03) 457-464
  • 15 Miyagawa S, Domae K, Yoshikawa Y. , et al. Phase I clinical trial of autologous stem cell-sheet transplantation therapy for treating cardiomyopathy. J Am Heart Assoc 2017; 6 (04) e003918
  • 16 Murry CE, Soonpaa MH, Reinecke H, Nakajima H, Nakajima HO, Rubart M. , et al. Haematopoietic stem cells do not transdifferentiate into cardiac myocytes in myocardial infarcts. Nature 2004; 428: 664-8 . doi:10.1038/nature02446.
  • 17 Balsam LB, Wagers AJ, Christensen JL, Kofidis T, Weissman IL, Robbins RC. Haematopoietic stem cells adopt mature haematopoietic fates in ischaemic myocardium. Nature 2004; 428: 668-73 . doi:10.1038/nature02460.
  • 18 Schächinger V, Erbs S, Elsässer A. , et al; REPAIR-AMI Investigators. 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 (23) 2775-2783
  • 19 Dill T, Schächinger V, Rolf A. , et al. Intracoronary administration of bone marrow-derived progenitor cells improves left ventricular function in patients at risk for adverse remodeling after acute ST-segment elevation myocardial infarction: results of the Reinfusion of Enriched Progenitor cells And Infarct Remodeling in Acute Myocardial Infarction study (REPAIR-AMI) cardiac magnetic resonance imaging substudy. Am Heart J 2009; 157 (03) 541-547
  • 20 Assmus B, Rolf A, Erbs S. , et al; REPAIR-AMI Investigators. Clinical outcome 2 years after intracoronary administration of bone marrow-derived progenitor cells in acute myocardial infarction. Circ Heart Fail 2010; 3 (01) 89-96
  • 21 Traverse JH, Henry TD, Pepine CJ. , et al; Cardiovascular Cell Therapy Research Network (CCTRN). 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 2012; 308 (22) 2380-2389
  • 22 Traverse JH, Henry TD, Pepine CJ. , et al; Cardiovascular Cell Therapy Research Network (CCTRN). 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 2012; 308 (22) 2380-2389
  • 23 Assmus B, Dimmeler S, Zeiher AM. Cardiac cell therapy: lost in meta-analyses. Circ Res 2015; 116 (08) 1291-1292
  • 24 Mathur A, Fernández-Avilés F, Dimmeler S. , et al; BAMI Investigators. The consensus of the Task Force of the European Society of Cardiology concerning the clinical investigation of the use of autologous adult stem cells for the treatment of acute myocardial infarction and heart failure: update 2016. Eur Heart J 2017; 38 (39) 2930-2935
  • 25 Pokushalov E, Romanov A, Chernyavsky A. , et al. Efficiency of intramyocardial injections of autologous bone marrow mononuclear cells in patients with ischemic heart failure: a randomized study. J Cardiovasc Transl Res 2010; 3 (02) 160-168
  • 26 Bartunek J, Behfar A, Dolatabadi D. , 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 2013; 61 (23) 2329-2338
  • 27 Bartunek J, Davison B, Sherman W. , et al. Congestive Heart Failure Cardiopoietic Regenerative Therapy (CHART-1) trial design. Eur J Heart Fail 2016; 18 (02) 160-168
  • 28 Bartunek J, Davison B, Sherman W. , et al. Congestive Heart Failure Cardiopoietic Regenerative Therapy (CHART-1) trial design. Eur J Heart Fail 2016; 18 (02) 160-168
  • 29 Henry TD, Traverse JH, Hammon BL. , et al. Safety and efficacy of ixmyelocel-T: an expanded, autologous multi-cellular therapy, in dilated cardiomyopathy. Circ Res 2014; 115 (08) 730-737
  • 30 Bartel RL, Cramer C, Ledford K. , et al. The Aastrom experience. Stem Cell Res Ther 2012; 3 (04) 26
  • 31 Patel AN, Henry TD, Quyyumi AA. , et al; ixCELL-DCM Investigators. Ixmyelocel-T for patients with ischaemic heart failure: a prospective randomised double-blind trial. Lancet 2016; 387 (10036): 2412-2421
  • 32 Patel AN, Geffner L, Vina RF. , et al. Surgical treatment for congestive heart failure with autologous adult stem cell transplantation: a prospective randomized study. J Thorac Cardiovasc Surg 2005; 130 (06) 1631-1638
  • 33 Losordo DW, Henry TD, Davidson C. , et al; ACT34-CMI Investigators. Intramyocardial, autologous CD34+ cell therapy for refractory angina. Circ Res 2011; 109 (04) 428-436
  • 34 Stamm C, Nasseri B, Hetzer R. Cardiac stem cells in patients with ischaemic cardiomyopathy. Lancet 2012; 379 (9819): 891-892 , author reply 891–892
  • 35 Noiseux N, Mansour S, Weisel R. , et al. The IMPACT-CABG trial: a multicenter, randomized clinical trial of CD133(+) stem cell therapy during coronary artery bypass grafting for ischemic cardiomyopathy. J Thorac Cardiovasc Surg 2016; 152 (06) 1582-1588.e2
  • 36 Nasseri BA, Ebell W, Dandel M. , et al. Autologous CD133+ bone marrow cells and bypass grafting for regeneration of ischaemic myocardium: the Cardio133 trial. Eur Heart J 2014; 35 (19) 1263-1274
  • 37 Donndorf P, Kaminski A, Tiedemann G, Kundt G, Steinhoff G. Validating intramyocardial bone marrow stem cell therapy in combination with coronary artery bypass grafting, the PERFECT Phase III randomized multicenter trial: study protocol for a randomized controlled trial. Trials 2012; 13 (01) 99
  • 38 Clifford DM, Fisher SA, Brunskill SJ. , et al. Long-term effects of autologous bone marrow stem cell treatment in acute myocardial infarction: factors that may influence outcomes. PLoS One 2012; 7 (05) e37373
  • 39 Dominici M, Le Blanc K, Mueller I. , et al. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy 2006; 8 (04) 315-317
  • 40 Shi S, Gronthos S. Perivascular niche of postnatal mesenchymal stem cells in human bone marrow and dental pulp. J Bone Miner Res 2003; 18 (04) 696-704
  • 41 Kinnaird T, Stabile E, Burnett MS. , et al. Marrow-derived stromal cells express genes encoding a broad spectrum of arteriogenic cytokines and promote in vitro and in vivo arteriogenesis through paracrine mechanisms. Circ Res 2004; 94 (05) 678-685
  • 42 Hoogduijn MJ. Are mesenchymal stromal cells immune cells?. Arthritis Res Ther 2015; 17 (01) 88
  • 43 Spaggiari GM, Capobianco A, Becchetti S, Mingari MC, Moretta L. Mesenchymal stem cell-natural killer cell interactions: evidence that activated NK cells are capable of killing MSCs, whereas MSCs can inhibit IL-2-induced NK-cell proliferation. Blood 2006; 107 (04) 1484-1490
  • 44 Glennie S, Soeiro I, Dyson PJ, Lam EW-F, Dazzi F. Bone marrow mesenchymal stem cells induce division arrest anergy of activated T cells. Blood 2005; 105 (07) 2821-2827
  • 45 Bourin P, Bunnell BA, Casteilla L. , et al. Stromal cells from the adipose tissue-derived stromal vascular fraction and culture expanded adipose tissue-derived stromal/stem cells: a joint statement of the International Federation for Adipose Therapeutics and Science (IFATS) and the International Society for Cellular Therapy (ISCT). Cytotherapy 2013; 15 (06) 641-648
  • 46 Iwase T, Nagaya N, Fujii T. , et al. Comparison of angiogenic potency between mesenchymal stem cells and mononuclear cells in a rat model of hindlimb ischemia. Cardiovasc Res 2005; 66 (03) 543-551
  • 47 Guillot PV, Gotherstrom C, Chan J, Kurata H, Fisk NM. Human first-trimester fetal MSC express pluripotency markers and grow faster and have longer telomeres than adult MSC. Stem Cells 2007; 25 (03) 646-654
  • 48 Nekanti U, Dastidar S, Venugopal P, Totey S, Ta M. Increased proliferation and analysis of differential gene expression in human Wharton's jelly-derived mesenchymal stromal cells under hypoxia. Int J Biol Sci 2010; 6 (05) 499-512
  • 49 Bieback K, Kern S, Klüter H, Eichler H. Critical parameters for the isolation of mesenchymal stem cells from umbilical cord blood. Stem Cells 2004; 22 (04) 625-634
  • 50 Hatzistergos KE, Quevedo H, Oskouei BN. , et al. Bone marrow mesenchymal stem cells stimulate cardiac stem cell proliferation and differentiation. Circ Res 2010; 107 (07) 913-922
  • 51 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 (06) 1919-1925 , discussion 1926
  • 52 Vrijsen KR, Maring JA, Chamuleau SA. , et al. Exosomes from cardiomyocyte progenitor cells and mesenchymal stem cells stimulate angiogenesis via EMMPRIN. Adv Healthc Mater 2016; 5 (19) 2555-2565
  • 53 Arslan F, Lai RC, Smeets MB. , et al. Mesenchymal stem cell-derived exosomes increase ATP levels, decrease oxidative stress and activate PI3K/Akt pathway to enhance myocardial viability and prevent adverse remodeling after myocardial ischemia/reperfusion injury. Stem Cell Res (Amst) 2013; 10 (03) 301-312
  • 54 Glenn JD, Whartenby KA. Mesenchymal stem cells: emerging mechanisms of immunomodulation and therapy. World J Stem Cells 2014; 6 (05) 526-539
  • 55 Fukuda K, Fujita J. Mesenchymal, but not hematopoietic, stem cells can be mobilized and differentiate into cardiomyocytes after myocardial infarction in mice. Kidney Int 2005; 68 (05) 1940-1943
  • 56 Ohtani K, Dimmeler S. Epigenetic regulation of cardiovascular differentiation. Cardiovasc Res 2011; 90 (03) 404-412
  • 57 Heldman AW, DiFede DL, Fishman JE. , et al. Transendocardial mesenchymal stem cells and mononuclear bone marrow cells for ischemic cardiomyopathy: the TAC-HFT randomized trial. JAMA 2014; 311 (01) 62-73
  • 58 Boquest AC, Shahdadfar A, Brinchmann JE, Collas P. Isolation of stromal stem cells from human adipose tissue. Methods Mol Biol 2006; 325: 35-46
  • 59 Rehman J, Traktuev D, Li J. , et al. Secretion of angiogenic and antiapoptotic factors by human adipose stromal cells. Circulation 2004; 109 (10) 1292-1298
  • 60 Miranville A, Heeschen C, Sengenès C, Curat CA, Busse R, Bouloumié A. Improvement of postnatal neovascularization by human adipose tissue-derived stem cells. Circulation 2004; 110 (03) 349-355
  • 61 Sengenès C, Miranville A, Maumus M, de Barros S, Busse R, Bouloumié A. Chemotaxis and differentiation of human adipose tissue CD34+/CD31- progenitor cells: role of stromal derived factor-1 released by adipose tissue capillary endothelial cells. Stem Cells 2007; 25 (09) 2269-2276
  • 62 Rodríguez LV, Alfonso Z, Zhang R, Leung J, Wu B, Ignarro LJ. Clonogenic multipotent stem cells in human adipose tissue differentiate into functional smooth muscle cells. Proc Natl Acad Sci U S A 2006; 103 (32) 12167-12172
  • 63 Gimble JM, Katz AJ, Bunnell BA. Adipose-derived stem cells for regenerative medicine. Circ Res 2007; 100 (09) 1249-1260
  • 64 Valina C, Pinkernell K, Song Y-H. , et al. Intracoronary administration of autologous adipose tissue-derived stem cells improves left ventricular function, perfusion, and remodelling after acute myocardial infarction. Eur Heart J 2007; 28 (21) 2667-2677
  • 65 Perin EC, Sanz-Ruiz R, Sánchez PL. , et al. Adipose-derived regenerative cells in patients with ischemic cardiomyopathy: the PRECISE Trial. Am Heart J 2014; 168 (01) 88-95.e2
  • 66 Comella K, Parcero J, Bansal H. , et al. Effects of the intramyocardial implantation of stromal vascular fraction in patients with chronic ischemic cardiomyopathy. J Transl Med 2016; 14 (01) 158
  • 67 Alt EU, Senst C, Murthy SN. , et al. Aging alters tissue resident mesenchymal stem cell properties. Stem Cell Res (Amst) 2012; 8 (02) 215-225
  • 68 Kern S, Eichler H, Stoeve J, Klüter H, Bieback K. Comparative analysis of mesenchymal stem cells from bone marrow, umbilical cord blood, or adipose tissue. Stem Cells 2006; 24 (05) 1294-1301
  • 69 Rebelatto CK, Aguiar AM, Moretão MP. , et al. Dissimilar differentiation of mesenchymal stem cells from bone marrow, umbilical cord blood, and adipose tissue. Exp Biol Med (Maywood) 2008; 233 (07) 901-913
  • 70 Nekanti U, Mohanty L, Venugopal P, Balasubramanian S, Totey S, Ta M. Optimization and scale-up of Wharton's jelly-derived mesenchymal stem cells for clinical applications. Stem Cell Res (Amst) 2010; 5 (03) 244-254
  • 71 Can A, Ulus AT, Cinar O. , et al. Human Umbilical Cord Mesenchymal Stromal Cell Transplantation in Myocardial Ischemia (HUC-HEART Trial). A study protocol of a phase 1/2, controlled and randomized trial in combination with coronary artery bypass grafting. Stem Cell Rev 2015; 11 (05) 752-760
  • 72 Ma N, Ladilov Y, Moebius JM. , et al. Intramyocardial delivery of human CD133+ cells in a SCID mouse cryoinjury model: bone marrow vs. cord blood-derived cells. Cardiovasc Res 2006; 71 (01) 158-169
  • 73 Cargnoni A, Di Marcello M, Campagnol M, Nassuato C, Albertini A, Parolini O. Amniotic membrane patching promotes ischemic rat heart repair. Cell Transplant 2009; 18 (10) 1147-1159
  • 74 Yuan W, Zong C, Huang Y. , et al. Biological, immunological and regenerative characteristics of placenta-derived mesenchymal stem cell isolated using a time-gradient attachment method. Stem Cell Res (Amst) 2012; 9 (02) 110-123
  • 75 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 (09) 911-921
  • 76 Lepilina A, Coon AN, Kikuchi K. , et al. A dynamic epicardial injury response supports progenitor cell activity during zebrafish heart regeneration. Cell 2006; 127 (03) 607-619
  • 77 Bearzi C, Rota M, Hosoda T. , et al. Human cardiac stem cells. Proc Natl Acad Sci U S A 2007; 104 (35) 14068-14073
  • 78 Goumans M-J, de Boer TP, Smits AM. , et al. TGF-beta1 induces efficient differentiation of human cardiomyocyte progenitor cells into functional cardiomyocytes in vitro. Stem Cell Res (Amst) 2007; 1 (02) 138-149
  • 79 Bearzi C, Rota M, Hosoda T. , et al. Human cardiac stem cells. Proc Natl Acad Sci U S A 2007; 104 (35) 14068-14073
  • 80 Matsuura K, Honda A, Nagai T. , et al. Transplantation of cardiac progenitor cells ameliorates cardiac dysfunction after myocardial infarction in mice. J Clin Invest 2009; 119 (08) 2204-2217
  • 81 Zwetsloot PP, Végh AM, Jansen of Lorkeers SJ. , et al. Cardiac stem cell treatment in myocardial infarction: a systematic review and meta-analysis of preclinical studies. Circ Res 2016; 118 (08) 1223-1232
  • 82 Bolli R, Chugh AR, D'Amario D. , et al. Cardiac stem cells in patients with ischaemic cardiomyopathy (SCIPIO): initial results of a randomised phase 1 trial. Lancet 2011; 378 (9806): 1847-1857
  • 83 Li T-S, Cheng K, Malliaras K. , et al. Direct comparison of different stem cell types and subpopulations reveals superior paracrine potency and myocardial repair efficacy with cardiosphere-derived cells. J Am Coll Cardiol 2012; 59 (10) 942-953
  • 84 Dehne T, Adam X, Materne E-M. , et al. A P19 and P19CL6 cell-based complementary approach to determine paracrine effects in cardiac tissue engineering. Cells Tissues Organs 2014; 199 (01) 24-36
  • 85 Haag M, Stolk M, Ringe J. , et al. Immune attributes of cardiac-derived adherent proliferating (CAP) cells in cardiac therapy. J Tissue Eng Regen Med 2013; 7 (05) 362-370
  • 86 Bian S, Zhang L, Duan L, Wang X, Min Y, Yu H. Extracellular vesicles derived from human bone marrow mesenchymal stem cells promote angiogenesis in a rat myocardial infarction model. J Mol Med (Berl) 2014; 92 (04) 387-397
  • 87 Gallet R, Dawkins J, Valle J. , et al. Exosomes secreted by cardiosphere-derived cells reduce scarring, attenuate adverse remodelling, and improve function in acute and chronic porcine myocardial infarction. Eur Heart J 2017; 38 (03) 201-211