Cardiac regeneration using stem cells emerges as a noveltreatment option for heart failure. Clinical applications havereported encouraging but modest favorable results, concerningcardiac functional recovery. However, many issues need clarification.The most appropriate cell type, the optimal number ofinjected cells and time for cell delivery, as well as the mode ofcell function remain to be elucidated. Furthermore, ways to improve cell survival and long term engraftment are being sought, in an effort to enhance the regenerative capability of the cells. A substantial amount of basic, translational and clinical research is still needed, in order to take advantage of the full therapeuticpotential of stem cell treatments for heart failure

Bonios, Michael J

Terrovitis, John V

Hospital Chronicles (E-Journal)

Heart Failure: Will There be Any Light at the End of the Tunnel with Stem Cell Therapy?Michael J. Bonios, John V. TerrovitisT h e  h e a r T  i s  n o T  a  T e r m i n a l l y  D i f f e r e n T i a T e D  o r g a nOver the last decade, numerous findings from experimental and clinical studies have challenged the paradigm that the heart is a post-mitotic organ and myocytes are terminally differentiated cells. Recently, two landmark papers have provided compelling evidence in favor of myocardial regeneration. Hsiech et al1 used a model of transgenic mice to demonstrate that replacement of adult mammalian cardiomyo-cytes takes place after injury but not during normal aging. Bergmann et al.2 using an elegant method of determining cardiomyocyte age, showed that even in humans, cardiomyocytes renew at very low rates, with a gradual decrease over the years (1% turnover annually at the age of 25, to 0.45% at the age of 75). Fewer than 50% of cardiomyocytes are exchanged during a normal life span. These findings emphasize the fact that the body’s innate ability to repair the heart is inadequate to compensate for a large myocardial injury.The ideal cell for myocardial regeneration should be easy to isolate and expand in vitro, available as an ‘of the shelf’ product and with differentiation potential. In addition, safety (no arrhythmias or tumor formation) should be demonstrated before any widespread clinical application. Currently, there is no cell with all these charac-teristics. However, several cell types, including skeletal myoblasts, bone marrow stem cells, adipose tissue mesechymal stem cells, embryonic stem cells and cardiac residing progenitor cells, have been used experimentally for myocardial regeneration.3s k e l e T a l  m y o b l a s T sSkeletal myoblasts were used very early in cell transplantation studies, due to their availability and ease for cell expansion. However, in clinical trials they have been proven arrhythmogenic and ineffective. In the randomized MAGIC trial4 the intramyocardial implantation of skeletal myoblasts in patients with ischemic heart disease and ejection fraction <35% failed to improve heart function and the study was terminated early.aThens CarDiology UPDaTe 20103rd Cardiology Department, University of Athens, Medical School, Athens, GreeceHOSPITAL CHRONICLES 2010, SUPPLEMENT: 48–50Correspondence to:John V. TerrovitisE-mail: john.terrovitis@gmail.comkey WorDs: myocardial regeneration; heart failure; cardiomyocytesHEART FAILURE: WILL THERE BE ANy LIGHT AT THE ENd OF THE TUNNEL WITH STEM CELL THERAPy?49b o n e  m a r r o W  a n D  P e r i P h e r a l C i r C U l a T i n g  P r o g e n i T o r  C e l l sBone marrow constitutes a source for a variety of progeni-tor cells like hemangioblasts, mesenchymal and multipotent adult progenitor cells.5 In a mouse myocardial infarction mod-el, Orlic et al6 reported that the injected bone marrow c-kit+ stem cells fully differentiated into cardiomyocytes, reduced infarct size and improved myocardial function. However, a subsequent carefully designed experimental study by Murry et al7 showed that the intramyocardially injected bone marrow stem cells very rarely, if ever, do they differentiate into cardio-myocytes, although they are able to improve myocardial func-tion, presumably through paracrine activity. In an elegantly designed study in transgenic animals, Alvarez-dolado et al8 provided evidence that cell fusion of bone marrow derived stem cells with cardiomyocytes was responsible for most of these supposedly ‘transdifferentiation’ events.Bone marrow derived stem cells have been tested exten-sively in clinical trials. In the randomized REPAIR AMI trial,9 intracoronary administration of bone marrow mononuclear cells was associated with improved recovery of left ventricular contractile function in patients after acute myocardial infarc-tion. Patients with the most severely depressed left ventricular ejection fraction (LVEF) derived the greatest benefit.Many clinical trials have been completed, assessing the efficacy of the intracoronary infusion of bone marrow derived stem cells or peripheral mononuclear cells in patients with a recent myocardial infarction. In a meta-analysis10 patients who received intracoronary cell therapy 3 to 7 days after successful reperfusion, had a significant, albeit modest, improvement in LVEF (3.0% increase [95% confidence interval (CI) 1.9 to 4.1]; p <0.001), as well as a reduction in infarct size (-5.6% [95% CI -8.7 to -2.5]; p <0.001).These encouraging but modest benefits may be explained by the lack of true transdifferention potential of these cells, precluding their engraftment in the heart and synchronization with native cardiomyocytes. Furthermore, the percentage of long term surviving cells in the host myocardium is small.11m e s e n C h y m a l  s T e m  C e l l sMesenchymal stem cells constitute another attractive stem cell population. Mesenchymal stem cells (MSCs) are multipo-tent cells found in several adult tissues. They do not express MHC class II proteins and transplanted allogeneic MSCs can be detected in recipients for a long period after delivery, indicating a lack of immune recognition and clearance.12Schuleri et al13 injected intramyocardially autologous bone marrow derived mesenchymal stem cells in a swine model, 12 week post-myocardial infarction. MSCs reduced infarct size and increased regional contractility and myocardial blood flow. In a phase 1 clinical study using intravenous adminis-tration of allogeneic MSCs derived from healthy donors, in patients after myocardial infarction, Hare et al14 confirmed the safety and efficacy of this therapy and reported encouraging preliminary findings concerning efficacy.C a r D i a C  P r o g e n i T o r  s T e m  C e l l sSeveral groups have reported the existence of resident car-diac stem cells that are able to differentiate into the main cardi-ac cell types (cardiomyocutes, smooth muscle and endothelial cells). Messina and colleagues first demonstrated that cardiac progenitors cells (CPCs) could be grown directly from cardiac tissue and further enriched after going through a tissue culture step that involved the formation of spherical aggregates, called cardiospheres.15 Extensive research in Eduardo Marban’s lab at Johns Hopkins University further advanced this method towards clinical translation, by developing a technique for expanding cells from these cardiospheres, in order to yield a sufficient amount of cardiosphere-derived cells (CdCs) with cardiogenic properties. Human CdCs injected into the border zone of myocardial infarcts in immunodeficient mice engrafted and reduced infarct size.16 Using in vivo imaging techniques17 and reporter genes the same group showed that only a fraction of the injected cells survive after the first few days following their delivery to the myocardium. In addition, they demonstrated that augmenting CdC retention resulted in greater improvement in cardiac function18.Johnston et al reported that CdCs administered via the intracoronary route were effective in ameliorating left ven-tricular remodeling after myocardial infarction, in a porcine model.19 These encouraging data from the preclinical studies with CdCs, lead to a phase I clinical study (NCT00893360), which investigates the feasibility and safety of intracoronary administration of autologous CdCs, in patients with decreased LVEF after myocardial infarction. Efficacy will also be as-sessed as a secondary end point.i n D U C e D  P l U r i P o T e n T  s T e m  C e l l sEmbryonic stem cells (ES) are the only cell type that fulfills the criteria of a real stem cell: pluripotency and self-renewal. However, their clinical application encounters severe obstacles, including ethical issues regarding their isolation from embryos. One way to circumvent these issues is to gener-ate pluripotent cells directly from somatic cells. Takahashi et al20 described a method where over-expression of four tran-scription factors, characteristic of ES cells, in mouse fibrob-lasts lead to the generation of ES-like pluripotent stem cells. The cells, named induced pluripotent stem (iPS) cells, could 50HOSPITAL CHRONICLES, SUPPLEMENT 2010be differentiated into cells of all three germ layers including cardiomyocytes. Recently, human iPS cells were successfully differentiated into cardiomyocytes in vitro.21 However, the development of methods for directing differentiation of these cells towards the desired cell line is still needed, in order to eliminate the danger for teratoma formation.21C o n C l U s i o nCardiac regeneration using stem cells emerges as a novel treatment option for heart failure. Clinical applications have reported encouraging but modest favorable results, concerning cardiac functional recovery. However, many issues need clarifi-cation. The most appropriate cell type, the optimal number of injected cells and time for cell delivery, as well as the mode of cell function (differentiation or paracrine mechanism) remain to be elucidated. Furthermore, ways to improve cell survival and long term engraftment are being sought, in an effort to enhance the regenerative capability of the cells. A substantial amount of basic, translational and clinical research is still needed, in order to take advantage of the full therapeutic potential of stem cell treatments for heart failure.r e f e r e n C e s 1. Hsieh PC, Segers VF, davis ME, et al. Evidence from a genetic fate-mapping study that stem cells refresh adult mammalian cardiomyocytes after injury. Nat Med 2007; 13:970-974. 2. Bergmann O, Bhardwaj Rd, Bernard S, et al. Evidence for car-diomyocyte renewal in humans. Science 2009; 324:98-102. 3. dimmeler S, Zeiher AM, Schneider Md. Unchain my heart: the scientific foundations of cardiac repair. J Clin Invest 2005; 115:572-583. 4. Menasche P, Alfieri O, Janssens S, et al. The Myoblast Autolo-gous Grafting in Ischemic Cardiomyopathy (MAGIC) trial: first randomized placebo-controlled study of myoblast transplanta-tion. Circulation 2008; 117:1189-1200. 5. Herzog EL, Chai L, Krause dS. Plasticity of marrow-derived stem cells. Blood 2003; 102:3483-3493. 6. Orlic d, Kajstura J, Chimenti S, et al. Bone marrow cells regen-erate infarcted myocardium. Nature 2001; 410:701-705. 7. 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. 8. Alvarez-dolado M, Pardal R, Garcia-Verdugo JM, et al. Fusion of bone-marrow-derived cells with Purkinje neurons, cardiomy-ocytes and hepatocytes. Nature 2003; 425:968-973. 9. 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. 10. Lipinski MJ, Biondi-Zoccai GG, Abbate A, et al. Impact of in-tracoronary cell therapy on left ventricular function in the set-ting of acute myocardial infarction: a collaborative systematic review and meta-analysis of controlled clinical trials. J Am Coll Cardiol 2007; 50:1761-1767. 11. Laflamme MA, Zbinden S, Epstein SE, Murry CE. Cell-based therapy for myocardial ischemia and infarction: pathophysi-ological mechanisms. Annu Rev Pathol 2007; 2:307-339. 12. Aggarwal S, Pittenger MF. Human mesenchymal stem cells modulate allogeneic immune cell responses. Blood 2005; 105:1815-1822. 13. Schuleri KH, Feigenbaum GS, Centola M, et al. Autologous mesenchymal stem cells produce reverse remodelling in chronic ischaemic cardiomyopathy. Eur Heart J 2009; 30:2722-2732. 14. Hare JM, Traverse JH, Henry Td, et al. A randomized, double-blind, 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. 15. 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. 16. Smith RR, Barile L, Cho HC, et al. Regenerative potential of cardiosphere-derived cells expanded from percutaneous en-domyocardial biopsy specimens. Circulation 2007; 115:896-908. 17. Terrovitis J, Kwok KF, Lautamaki R, et al. Ectopic expression of the sodium-iodide symporter enables imaging of transplanted cardiac stem cells in vivo by single-photon emission computed tomography or positron emission tomography. J Am Coll Car-diol 2008; 52:1652-1660. 18. Terrovitis J, Lautamaki R, Bonios M, et al. Noninvasive quanti-fication and optimization of acute cell retention by in vivo posi-tron emission tomography after intramyocardial cardiac-derived stem cell delivery. J Am Coll Cardiol 2009; 54:1619-1626. 19. Johnston PV, Sasano T, Mills K, et al. Engraftment, differen-tiation, and functional benefits of autologous cardiosphere-derived cells in porcine ischemic cardiomyopathy. Circulation 2009; 120:1075-1083, 7 p following 83. 20. Takahashi K, Okita K, Nakagawa M, yamanaka S. Induction of pluripotent stem cells from fibroblast cultures. Nat Protoc 2007; 2:3081-3089. 21. Zwi L, Caspi O, Arbel G, et al. Cardiomyocyte differentiation of human induced pluripotent stem cells. Circulation 2009; 120:1513-1523.

Heart Failure: Will There be Any light at the End of the Tunnel with Stem Cell Therapy?

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Heart Failure: Will There be Any light at the End of the Tunnel with Stem Cell Therapy?

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