Cell Therapy for Heart Disease
2011; Lippincott Williams & Wilkins; Volume: 108; Issue: 4 Linguagem: Inglês
10.1161/circresaha.111.240218
ISSN1524-4571
AutoresMuzammil Mushtaq, Behzad N. Oskouei, Joshua M. Hare,
Tópico(s)Tissue Engineering and Regenerative Medicine
ResumoHomeCirculation ResearchVol. 108, No. 4Cell Therapy for Heart Disease Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBCell Therapy for Heart DiseaseTo Genetically Modify or Not, That Is the Question Muzammil Mushtaq, Behzad N. Oskouei and Joshua M. Hare Muzammil MushtaqMuzammil Mushtaq From The Philip and Suzi Rudd Cohen Cardiovascular Research Laboratory in Honor of Dr Joshua Hare, Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, FL. , Behzad N. OskoueiBehzad N. Oskouei From The Philip and Suzi Rudd Cohen Cardiovascular Research Laboratory in Honor of Dr Joshua Hare, Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, FL. and Joshua M. HareJoshua M. Hare From The Philip and Suzi Rudd Cohen Cardiovascular Research Laboratory in Honor of Dr Joshua Hare, Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, FL. Originally published18 Feb 2011https://doi.org/10.1161/CIRCRESAHA.111.240218Circulation Research. 2011;108:398–401See related article, pages 478–489Cell-based therapy for heart diseases, ranging from myocardial infarction, hibernating myocardium, to ischemic and nonischemic cardiomyopathies, is a potentially transformative approach to address unmet needs for the treatment of these chronic diseases.1 As this field moves forward rapidly, pressing questions continue to require resolution. Of these, perhaps the most pressing question is what are the features of an ideal cell type to be used for cardiovascular therapeutics.1In this context, several investigative teams have undertaken the approach of starting with a reasonable candidate cell, whether that be an adult stem cell, such as a mesenchymal stem cell2 (MSC) or cardiac stem cell (CSC),3,4 or a pluripotent stem cell,5 and then enhancing that cell by genetic modification or incubation with factors or cytokines6 capable of optimizing the ability of the cell to engraft, survive, and/or differentiate. This approach has uniformly produced positive results using MSCs and CSCs with a number of genetic modifications (Table).Table. Impact of Modification of MSCs or CSCs on Phenotypic OutcomeInterventionSpeciesVector or Means of OverexpressionResultsWnt1123RatPlasmid Murine Stem Cell Virus (pMSCV)Enhanced MSC differentiation into cardiac phenotypesChemokine (C-C motif) receptor 124 (CCR1)MousepMSCVReduced cell apoptosis and infarction siteIncreased capillary densityPrevention of remodelingRestoration of cardiac functionTransforming growth factor-α25 (TGF-α)MousePreconditioning with TGF-αVascular endothelial growth factor (VEGF) productionPostischemic myocardial recoveryConnexin4326 (Cx 43)RatPlasmid pRNA-U6-neovectorReduced infarction sizeImproved contractile performanceSurvivin27 (SVV)RatLentivirusReduced infarction sizeEnhanced VEGF productionInhibit myocardial remodelingEnhanced cell survivalTumor necrosis factor receptor28 (TNRF)RatPlasmid rAAVInhibited cardiac myocyte apoptosisImproved left ventricular functionHuman angiopoietin-129 (hANg1)RatPlasmidIncreased capillary densityReduced infarct sizePim-1 kinase3,4 (Pim-1)MouseLentivirusIncreased cardiac progenitor cell (CPC) proliferationCPC differentiated into cardiac, endothelial and smooth muscle lineagesImproved cardiac function, reduced infarct sizeAkt30,31Rat30pMSCVReduced apoptosisReduced infarct volumePig31AdenovirusNormalized cardiac functionPrevented remodelingIn this issue of Circulation Research, Cho et al show that overexpression of the serine/threonine kinase glycogen synthase kinase (GSK)-3β enhances the therapeutic properties of bone marrow–derived MSCs in a mouse model of myocardial infarction.7 These encouraging findings add to a growing list of kinases, the overexpression of which enhances MSC engraftment and differentiation into myocytes.These sets of experiments are highly valuable to help elucidate key signaling pathways involved in cell engraftment and differentiation. They also highlight a growing dilemma for translational research, ranging from preclinical large animal experimentation and early proof of concept clinical trials, that dilemma being a large number of candidate cell preparation approaches from which to choose (Table).Mechanism of ActionThe study by Cho et al7 reveals some major conceptual advances regarding MSC engraftment and differentiation, and the relationship between various cellular phenotypic outcomes and overall animal survival and/or left ventricular (LV) functional recovery (Figure). In this regard, Cho et al use the model to dissect the impact of MSC secretion of vascular endothelial growth factor (VEGF)-A8 and subsequent neovascularization on overall animal outcome, showing that myocyte differentiation and myocardial infarction size reduction still occur with VEGF-A being reduced, but that in the absence of neovascularization animal survival does not improve (Figure). This observation links nicely to large animal findings showing the importance of new blood vessel formation and tissue perfusion in response to MSC therapy.9,10Download figureDownload PowerPointFigure. Overexpression of GSK-3β induces cardiac differentiation of MSCs and also stimulates activation of endogenous c-kit+ cardiac precursors. Also part of their beneficial effect is a paracrine effect via upregulated secretion of VEGF-A and induction of vasculogenesis in the infarcted heart. In addition, GSK-3β MSCs show suppressed apoptosis. In the absence of VEGF-A, new myocyte formation still occurs, yet neovascularization is deficient and animal survival is no longer improved.The fact that GSK-3β overexpression enhances MSC survival after 8 weeks, promotes MSC differentiation into cardiac myocytes, and does so in a manner that promotes survival following infarction is extremely exciting and argues well for the use of these cells in the clinical setting.11,12 Paradoxically, in the heart inhibition of the GSK-3β has been shown to prevent cardiac remodeling and promote cardiac regeneration.13 This interesting dichotomy suggests important differences in GSK-3β signaling in the adult myocyte versus precursor cells.Translational DilemmaAlthough there is and should be substantial optimism regarding the translational development of cell therapeutics, the present study raises the key question of whether genetic modification of precursor cells will lead to a durable therapeutic strategy. Indeed, it is worthwhile in this context to note that carefully designed and conducted large animal experiments reveal many of the salutary effects seen with the GSK-3β MSCs in the present murine model. In pigs with acute or chronic myocardial infarction, unmodified native MSCs engraft,9,14,15 differentiate,14,15 improve LV function,9,14 offset or reverse ventricular remodeling,16 and improve myocardial systolic and diastolic function as well as mechanoenergetic coupling.9 Similar observations are reported using cardiosphere-derived cells.17 These findings have led to the conduct and design of ongoing clinical trials that reveal similar encouraging results in humans with acute myocardial infarction18 and chronic ischemic cardiomyopathy.19The fact that results in porcine models with wild-type cells appears better than in rodents speak to the possibility of species differences.20 Alternatively, these findings raise the issue that relevant pathways, such as GSK-3β, may already be activated in the setting of the large animal studies. A final consideration is one purely in the realm of reduction to practice in the clinic: that of cell delivery. The use of catheter delivery of large boluses of cells may enhance engraftment or activation of the cells.12 These exciting new hypotheses need to be tested in preclinical models.Fundamentally, the experiments of Cho et al7 help greatly to refine the issues crucial to the translation of cell therapy. Establishing the superiority of GSK-3β transduced cells relative to unmodified cells will require direct head-to-head comparisons in relevant large animal models and then proof of concept testing in humans. The introduction of genetically modified cells into human studies raises regulatory issues because the safety profile of that approach will require rigorous scrutiny. Other approaches are rapidly emerging as well, including cytokine incubation,6 the use of MSC precursors,21 and the use of CSCs.22To the extent that genetically modified cells make their way to the clinic, the choice of vector chosen to transduce the cells will be of increased importance so as to minimize potential negative consequences of unregulated overexpression. Clearly, as supported by the work of Cho et al,7 the totality of emerging evidence suggests that preconditioning cells with cytokine incubation or with genetic modification has potential merit in advancing the therapeutic potential of cell-based therapy. It is only with direct rigorous head-to-head testing that the translation to the clinic of genetically modified cells can be justified. Whether or not this is justified, the work of Cho et al has raised some critical and interesting questions regarding the biology of MSCs in general, vis a vis their function and efficacy.Non-standard Abbreviations and Acronyms CSCcardiac stem cellGSKglycogen synthase kinaseLVleft ventricularMSCmesenchymal stem cellVEGFvascular endothelial growth factorSources of FundingThis work was supported by National Heart, Lung, and Blood Institute grants U54-HL081028 (Specialized Center for Cell Based Therapy), R01-HL084275, and P20 HL101443. J.M.H. is also supported by R01 grants AG025017, HL065455, and HL094849.DisclosuresNone.FootnotesThe opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.Correspondence to Joshua M. Hare, MD, Louis Lemberg Professor, University of Miami Miller School of Medicine, Interdisciplinary Stem Cell Institute, 1501 NW 10th St, Suite 824, Miami, FL 33136. E-mail [email protected]miami.eduReferences1. 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Kanashiro-Takeuchi R, Schulman I and Hare J (2011) Pharmacologic and genetic strategies to enhance cell therapy for cardiac regeneration, Journal of Molecular and Cellular Cardiology, 10.1016/j.yjmcc.2011.05.015, 51:4, (619-625), Online publication date: 1-Oct-2011. February 18, 2011Vol 108, Issue 4 Advertisement Article InformationMetrics © 2011 American Heart Association, Inc.https://doi.org/10.1161/CIRCRESAHA.111.240218PMID: 21335427 Originally publishedFebruary 18, 2011 PDF download Advertisement SubjectsMyocardial Biology
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