What Is the Oncologic Risk of Stem Cell Treatment for Heart Disease?
2011; Lippincott Williams & Wilkins; Volume: 108; Issue: 11 Linguagem: Inglês
10.1161/circresaha.111.246611
ISSN1524-4571
AutoresKonstantinos E. Hatzistergos, Arnon Blum, Tan A. Ince, James M. Grichnik, Joshua M. Hare,
Tópico(s)Neuroblastoma Research and Treatments
ResumoHomeCirculation ResearchVol. 108, No. 11What Is the Oncologic Risk of Stem Cell Treatment for Heart Disease? Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBWhat Is the Oncologic Risk of Stem Cell Treatment for Heart Disease? Konstantinos E. Hatzistergos, Arnon Blum, Tan A. Ince, James M. Grichnik and Joshua M. Hare Konstantinos E. HatzistergosKonstantinos E. Hatzistergos From the Department of Pathology (T.A.I.), Interdisciplinary Stem Cell Institute (K.E.H., A.B., J.G., JMH), Sylvester Cancer Center (T.A.I., J.G.), Braman Family Breast Cancer Institute (T.A.I.), and Department of Medicine, Cardiovascular Division (J.M.H.), Leonard M. Miller School of Medicine, University of Miami, Miami, Florida. , Arnon BlumArnon Blum From the Department of Pathology (T.A.I.), Interdisciplinary Stem Cell Institute (K.E.H., A.B., J.G., JMH), Sylvester Cancer Center (T.A.I., J.G.), Braman Family Breast Cancer Institute (T.A.I.), and Department of Medicine, Cardiovascular Division (J.M.H.), Leonard M. Miller School of Medicine, University of Miami, Miami, Florida. , Tan A. InceTan A. Ince From the Department of Pathology (T.A.I.), Interdisciplinary Stem Cell Institute (K.E.H., A.B., J.G., JMH), Sylvester Cancer Center (T.A.I., J.G.), Braman Family Breast Cancer Institute (T.A.I.), and Department of Medicine, Cardiovascular Division (J.M.H.), Leonard M. Miller School of Medicine, University of Miami, Miami, Florida. , James M. GrichnikJames M. Grichnik From the Department of Pathology (T.A.I.), Interdisciplinary Stem Cell Institute (K.E.H., A.B., J.G., JMH), Sylvester Cancer Center (T.A.I., J.G.), Braman Family Breast Cancer Institute (T.A.I.), and Department of Medicine, Cardiovascular Division (J.M.H.), Leonard M. Miller School of Medicine, University of Miami, Miami, Florida. and Joshua M. HareJoshua M. Hare From the Department of Pathology (T.A.I.), Interdisciplinary Stem Cell Institute (K.E.H., A.B., J.G., JMH), Sylvester Cancer Center (T.A.I., J.G.), Braman Family Breast Cancer Institute (T.A.I.), and Department of Medicine, Cardiovascular Division (J.M.H.), Leonard M. Miller School of Medicine, University of Miami, Miami, Florida. Originally published27 May 2011https://doi.org/10.1161/CIRCRESAHA.111.246611Circulation Research. 2011;108:1300–1303is corrected byCorrectionSee related article, pages 1340–1347Every therapy has toxic and therapeutic windows, and defining the side effects of any new therapeutic modality is the first order of business in the development of a treatment. With transformative therapies such as cell-based approaches, treatment side effects can be unpredictable and unanticipated. In some cases, experimental data raise serious concerns that must be appropriately managed. In the face of the promise and enthusiasm for cell-based therapy for heart disease, results from rodent experiments have consistently raised the specter of a dreaded side effect—can the use of stem cells lead to cancer, either directly or through promotion of existing early-stage neoplasms?Mesenchymal stem cells (MSCs) are a multipotent immunotolerant cell source that can be readily expanded into therapeutic quantities from a variety of tissues such as the bone marrow, cord blood, and fat, and as such their use in cell-based therapeutic strategies holds great promise.1 With regard to heart disease, accumulating preclinical2–11 and clinical studies12–15 demonstrate that MSC transplantation may be salutary for both acute myocardial infarction and cardiomyopathy with an acceptable risk profile.The translational development of cell-based therapy has required rigorous large-animal experimentation, recognizing inherent limitations with rodent experimentation. In this context, more than 500 large animals (swine, canine, and sheep) have been tested to assess the safety and efficacy of MSC therapeutics for treating heart disease with the results demonstrating that MSC transplantation is a safe and durable approach that may be more effective than bone marrow mononuclear cells.16 Importantly, large-animal work provides a phenotyping opportunity not available in rodents, and rigorous cardiac MRI (CMR) and histological analysis in porcine hearts supported the regenerative effects subsequently demonstrated in the adult human heart.12,15 The mechanism of action appears multifaceted, involving direct differentiation of MSCs into cardiomyocytes and vessels,2,11 but to a greater extent, stimulation of the hearts' own cardiac stem cells to form new cardiac muscle.11Chromosomal Instability and the Risk of Neoplastic TransformationIn the face of these exciting preclinical and clinical findings, a series of concerning reports demonstrate that murine MSCs are prone to chromosomal abnormalities and promote tumor or ectopic tissue formation. The key reports include those of Miura et al,17 Breitbach et al,18 Foudah et al,19 and in the current issue of Circulation Research that of Jeong and colleagues.20 Miura et al showed that murine MSCs, after numerous passages, obtained unlimited population doublings and underwent malignant transformation; passage 65 MSCs injected into mice formed fibrosarcomas in multiple organs, including the pericardium. Raising additional concerns, Breitbach et al reported that murine MSCs and whole bone marrow led to unwanted tissue differentiation in the form of extensive bone formation in infarcted mouse hearts. Foudah et al also reported that rat MSCs (rMSCs) exhibited genomic instability and tumorigenicity in culture. However, "considering the apparent genomic stability reported for in vitro cultured human MSCs (hMSCs)," they concluded that "these findings underline the fact that rMSCs may not in fact be a good model for effectively exploring the full clinical therapeutic potential of hMSCs."The new report by Jeong et al extends these findings by showing that murine MSCs exhibit genetic instabilities even at low passages and lead to massive tumor formation in the heart and hindlimbs of mice. Chromosomal analysis revealed that culturing of these otherwise normal appearing, tumorigenic mouse MSCs caused multiple chromosomal abnormalities, including fusion, fragmentation, and ring formation. Considering the rarity (≈0.017%) of primary cardiac neoplasms in the human heart,21 the aggressiveness and size of the tumors that Jeong et al describe in ≈33% of the MSC-injected mouse hearts (a ≈2,000-fold increase in tumorigenic frequency) highlight the importance of potential interspecies variability in translational research. Nevertheless, these reports must be taken very seriously.With regard to the molecular underpinnings of transformation, an increased susceptibility of rodent versus human cells is described. Rangarajan et al22 demonstrated that whereas perturbation of 6 signaling pathways in human fibroblasts was required for tumorigenic transformation, mouse fibroblasts required only 2 (p53 and Raf). Considering that a typical random mutation rate is 10x−6 to 10x−7 per gene per somatic cell division, having 6 pathways mutated subtantially lowers the probability and provides a potential mechanism for the greatly increased resilience of cultured human cells in comparison with rodents.23 Thus, taking into account the caveat that these studies were performed in fibroblasts and not MSCs, per se, there appears to be a molecular basis for a decreased vulnerability of human cells to molecular transformation during culture expansion.An additional mechanism for MSC-stimulated promotion of neoplasia has been described. MSCs integrate within the tumor-associated stroma in conditions such as breast cancer24 and sarcomas,25,26 and therefore the possibility that human MSCs could also undergo chromosomal transformations that promote growth or increase the metastatic potency of a tumor is being extensively studied. These findings raise the concern that MSCs could track to areas of early malignant transformation in the body and promote or accelerate tumor formation. However, the study by Jeong et al clearly illustrates how studies of rodent cells in rodent models of disease may not be the appropriate strategy for addressing the risk of neoplasia in humans and underscores the fact that more reliable approaches, including large animal models or implantation of human cells into immunocompromised mice, should be used to rigorously gauge the risk of any adverse effect of a new therapeutic modality.Efficacy of Rodent Versus Human MSCsA further consideration strongly supports major differences between rodent and human MSCs, such that they may not recapitulate large mammalian biology with regard to regenerative performance. The findings of efficacy of cell-based therapy are consistently reported to be less than those seen in large animals or humans.18,27,28 For example, while human and porcine wild-type MSCs are capable of regenerating scarred myocardium in both direct and indirect manners,2,11,29–32 mouse and rat MSCs need to be genetically modified for enhanced survival or differentiation capacity to exert similar therapeutic effects.28,33–36 Furthermore, rodent MSCs are postulated to exert their effects largely through paracrine signaling, because their in vivo differentiation into cardiomyocytes has been difficult to demonstrate.35,37,38 Finally there are clear biological differences between rodent and human MSCs.39–41 For example, murine MSCs express sca-1 abundantly,20 whereas the human orthologue is yet to be described. Thus rodent and human MSCs differ at multiple levels.What Is the Risk of Human MSC Transformation?Unlike the several reports described above, human MSCs demonstrate substantial stability even when cultured ex vivo for long term, and direct evidence for spontaneous laboratory-induced transformations in human MSCs has not been definitively provided.In an influential report, Rubio and colleagues42 reported that long-term in vitro culturing of human adipose tissue–derived MSCs over a period of 4 to 5 months could transform them into "mutant stem cells that may seed cancer." When the transformed human MSCs were transplanted into immunocompromised mice, they generated cancers in nearly all mouse organs—including the heart—within 4 to 6 weeks. Therefore, the authors recommended that MSCs should not be considered safe for clinical testing. At the time when this article was published, we stopped our clinical trials of MSCs for a very careful review of the existing state of knowledge. After a careful review of the available large-animal data at the time and with additional safeguards, the trial was recommended for continuation and was completed. Ironically, this study was subsequently retracted by the authors43 because they were "unable to reproduce some of the reported spontaneous transformation events and suspect the phenomenon is due to a cross-contamination artifact." It was later reported that, indeed, the transformed cells in Rubio's report originated from cross-contamination with the fibrosarcoma cell line HT1080.44In a similar vein, Rosland et al45 reported that prolonged cultured human MSCs from the bone marrow could frequently undergo spontaneous malignant transformations. However, more rigorous DNA analysis highlighted that their human MSC cultures were also cross-contaminated with human fibrosarcoma or osteosarcoma cell lines.44 Moreover, in the case of clinical studies, all human MSCs lines are manufactured under certified good manufacturing practice (GMP) facilities and used from passage 1 (autologous transplant15) up to passage 5 (heterologous transplant12), therefore excluding any risk for long-term culturing or cultured-induced chromosomal instabilities or mutations. Accordingly, Wang and coworkers generated more than 100 human MSC lines, of which 1 yielded a transformed population. Of crucial importance, however, was that this transformed cell was present in the original bone marrow sample and expanded with time in culture, suggesting that it was actually a transformed line isolated from the patient. The tumorogenic population could be clearly distinguished from the MSC population by morphology and demonstrated an abnormal karyotype.46Together, this series of findings very strongly supports the safety of human MSCs in clinical trials, albeit with ongoing and extreme vigilance.Addressing the Risk of Neoplasia from Cell TherapyHow do we interpret these findings and what is the appropriate response? First, it should be recognized that the risk of neoplasia from stem cells, particularly MSCs, has long been recognized and managed in clinical trial development. In the case of MSCs, long-term studies in porcine models have used whole-body autopsies to establish that MSC-based therapies for heart disease do not bear a major unacceptable risk for ectopic tissue formation.2,6–11,47 Very importantly, phase I clinical trials have specifically monitored for unwanted tissue formation, including neoplasia. In both the Osiris sponsored phase I trial and a series of studies led by our group, whole-body computed tomography (CT) has been performed to monitor for this side effect.12,15 In addition, patients with increased oncological risk due to underlying comorbidities—such as HIV, hepatitis, hematologic disorders, or history of malignancy—have been excluded by trial design.12,15Results of Preclinical and Clinical StudiesCareful monitoring for adverse effects of MSC-based therapies in preclinical2,6–11,47 and clinical settings12,15 very strongly supports an acceptable safety profile for MSC therapeutics with regard to cancer or ectopic tissue formation. Importantly, our findings are supported by the work of many other laboratories (see the meta-analyis of Van der Spoel et al16). By studying more than 150 swine in our laboratory during a 10-year period using different MSC preparations and methods of delivery to the heart, we monitored the safety and efficacy of our treatment using cardiac MRI and whole-body histological analysis. In these studies, tumors (cardiac or otherwise) or ectopic tissue formation have not been observed. These findings contributed to the design and conduct of 4 clinical trials (the TAC-HFT [NCT00768066], POSEIDON [NCT01087996], Provacel [NCT00114452], and PROMETHEUS [NCT00587990]) that have recruited in the past 5 years more than 125 patients; a major risk of tumor growth has not been detected in these patients. In addition, numerous trials are ongoing for MSCs in multiple disease areas, including but not limited to graft versus host disease, ulcerative cholitis, chronic obstructive lung disease, and osteogenesis imperfecta. Ongoing phase I cardiac studies will add substantially to the database of safety information (sustained ventricular arrhythmias, ectopic tissue formation, or sudden unexpected death) and will begin to build the case for efficacy in patients with acute12 and chronic15 heart disease. At the same time, more than 700 patients with heart disease have received cell-based therapies with whole bone marrow in the last 10 years at different medical centers worldwide. No indications of tumor outgrowth have ever been reported, substantiating the concept that the risk for primary cancer development following bone marrow–based cellular cardiomyoplasty is minimal.SummaryAccumulating clinical and preclinical trials are adding to the database, supporting the idea that human cell therapy with MSC transplantation is a safe and a reliable procedure for treating heart disease. Long-term rigorous patient monitoring demonstrates the durability and safety of cell-based therapies for heart disease, with no incidence of tumorigenesis. As with any new therapy, extreme vigilance is required to monitor for, manage, and understand the risk of unwanted and desirable side effects. The specter of neoplasia raises major concerns. However, we conclude that the observations in rodent animal models used to study human diseases should be interpreted with caution when assessing safety and efficacy of any new therapeutic modality and that the risk–benefit profile of MSC cell therapy in the rodent is substantially different from that in large mammals. We believe that ongoing trials of MSCs in humans are of acceptable risk, but strongly argue for ongoing vigilance, particularly over the long term.Nonstandard Abbreviations and Acronyms CMRcardiac magnetic resonance imagingCTcomputed tomographyGMPgood manufacturing practicehMSCshuman mesenchymal stem cellsMSCsmesenchymal stem cellsrMSCsrodent mesenchymal stem cellsSources 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. Dr. Hare is also supported by RO1'sAG025017, HL065455, and HL094849.DisclosuresDr Grichnik discloses that he is a major shareholder in DigitalDerm, Inc, and a consultant for both Spectral Image, Inc, and Genentech, Inc. The remaining authors have nothing to disclose.FootnotesCorrespondence to Joshua M. Hare, MD, Leonard M. Miller School of Medicine, University of Miami, Interdisciplinary Stem Cell Institute, 1501 NW 10th Street, Suite 824, Miami, FL 33136. E-mail [email protected]miami.eduReferences1. Pittenger MF, Mackay AM, Beck SC, Jaiswal RK, Douglas R, Mosca JD, Moorman MA, Simonetti DW, Craig S, Marshak DR. Multilineage potential of adult human mesenchymal stem cells. Science. 1999; 284:143–147.CrossrefMedlineGoogle Scholar2. Quevedo HC, Hatzistergos KE, Oskouei BN, Feigenbaum GS, Rodriguez JE, Valdes D, Pattany PM, Zambrano JP, Hu Q, McNiece I, Heldman AW, Hare JM. Allogeneic mesenchymal stem cells restore cardiac function in chronic ischemic cardiomyopathy via trilineage differentiating capacity. Proc Natl Acad Sci U S A. 2009; 106:14022–14027.CrossrefMedlineGoogle Scholar3. Zhou Y, Wang S, Yu Z, Hoyt RF, Sachdev V, Vincent P, Arai AE, Kwak M, Burkett SS, Horvath KA. Direct injection of autologous mesenchymal stromal cells improves myocardial function. Biochem Biophys Res Commun. 2009; 390:902–907.CrossrefMedlineGoogle Scholar4. Barallobre-Barreiro J, de Ilarduya OM, Moscoso I, Calvino-Santos R, Aldama G, Centeno A, Lopez-Pelaez E, Domenech N. Gene expression profiles following intracoronary injection of mesenchymal stromal cells using a porcine model of chronic myocardial infarction. Cytotherapy. 2011; 13:407–418.CrossrefMedlineGoogle Scholar5. Bhakta S, Greco NJ, Finney MR, Scheid PE, Hoffman RD, Joseph ME, Banks JJ, Laughlin MJ, Pompili VJ. The safety of autologous intracoronary stem cell injections in a porcine model of chronic myocardial ischemia. J Invasive Cardiol. 2006; 18:212–218.MedlineGoogle Scholar6. Amado LC, Saliaris AP, Schuleri KH, St JM, Xie JS, Cattaneo S, Durand DJ, Fitton T, Kuang JQ, Stewart G, Lehrke S, Baumgartner WW, Martin BJ, Heldman AW, Hare JM. Cardiac repair with intramyocardial injection of allogeneic mesenchymal stem cells after myocardial infarction. Proc Natl Acad Sci U S A. 2005; 102:11474–11479.CrossrefMedlineGoogle Scholar7. Amado LC, Schuleri KH, Saliaris AP, Boyle AJ, Helm R, Oskouei B, Centola M, Eneboe V, Young R, Lima JA, Lardo AC, Heldman AW, Hare JM. Multimodality noninvasive imaging demonstrates in vivo cardiac regeneration after mesenchymal stem cell therapy. J Am Coll Cardiol. 2006; 48:2116–2124.CrossrefMedlineGoogle Scholar8. 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.CrossrefMedlineGoogle Scholar9. Schuleri KH, Amado LC, Boyle AJ, Centola M, Saliaris AP, Gutman MR, Hatzistergos KE, Oskouei BN, Zimmet JM, Young RG, Heldman AW, Lardo AC, Hare JM. Early improvement in cardiac tissue perfusion due to mesenchymal stem cells. Am J Physiol Heart Circ Physiol. 2008; 294:H2002–H2011.CrossrefMedlineGoogle Scholar10. Schuleri KH, Feigenbaum GS, Centola M, Weiss ES, Zimmet JM, Turney J, Kellner J, Zviman MM, Hatzistergos KE, Detrick B, Conte JV, McNiece I, Steenbergen C, Lardo AC, Hare JM. Autologous mesenchymal stem cells produce reverse remodelling in chronic ischaemic cardiomyopathy. Eur Heart J. 2009; 30:2722–2732.CrossrefMedlineGoogle Scholar11. Hatzistergos KE, Quevedo H, Oskouei BN, Hu Q, Feigenbaum GS, Margitich IS, Mazhari R, Boyle AJ, Zambrano JP, Rodriguez JE, Dulce R, Pattany PM, Valdes D, Revilla C, Heldman AW, McNiece I, Hare JM. Bone marrow mesenchymal stem cells stimulate cardiac stem cell proliferation and differentiation. Circ Res. 2010; 107:913–922.LinkGoogle Scholar12. Hare JM, Traverse JH, Henry TD, Dib N, Strumpf RK, Schulman SP, Gerstenblith G, DeMaria AN, Denktas AE, Gammon RS, Hermiller JB, Reisman MA, Schaer GL, Sherman W. 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.CrossrefMedlineGoogle Scholar13. Chen SL, Fang WW, Ye F, Liu YH, Qian J, Shan SJ, Zhang JJ, Chunhua RZ, Liao LM, Lin S, Sun JP. 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.CrossrefMedlineGoogle Scholar14. Katritsis DG, Sotiropoulou PA, Karvouni E, Karabinos I, Korovesis S, Perez SA, Voridis EM, Papamichail M. Transcoronary transplantation of autologous mesenchymal stem cells and endothelial progenitors into infarcted human myocardium. Catheter Cardiovasc Interv. 2005; 65:321–329.CrossrefMedlineGoogle Scholar15. Williams AR, Trachtenberg B, Velazquez DL, McNiece I, Altman P, Rouy D, Mendizabal AM, Pattany PM, Lopera GA, Fishman J, Zambrano JP, Heldman AW, Hare JM. Intramyocardial stem cell injection in patients with ischemic cardiomyopathy: functional recovery and reverse remodeling. Circ Res. 2011; 108:792–796.LinkGoogle Scholar16. van der Spoel TI, Jansen of Lorkeers SJ, Agostoni P, van BE, Gyongyosi M, Sluijter JP, Cramer MJ, Doevendans PA, Chamuleau SA. Human relevance of pre-clinical studies in stem cell therapy: systematic review and meta-analysis of large animal models of ischemic heart disease. Cardiovasc Res. 2011; In press.CrossrefMedlineGoogle Scholar17. Miura M, Miura Y, Padilla-Nash HM, Molinolo AA, Fu B, Patel V, Seo BM, Sonoyama W, Zheng JJ, Baker CC, Chen W, Ried T, Shi S. Accumulated chromosomal instability in murine bone marrow mesenchymal stem cells leads to malignant transformation. Stem Cells. 2006; 24:1095–1103.CrossrefMedlineGoogle Scholar18. Breitbach M, Bostani T, Roell W, Xia Y, Dewald O, Nygren JM, Fries JW, Tiemann K, Bohlen H, Hescheler J, Welz A, Bloch W, Jacobsen SE, Fleischmann BK. Potential risks of bone marrow cell transplantation into infarcted hearts. Blood. 2007; 110:1362–1369.CrossrefMedlineGoogle Scholar19. Foudah D, Redaelli S, Donzelli E, Bentivegna A, Miloso M, Dalpra L, Tredici G. Monitoring the genomic stability of in vitro cultured rat bone-marrow-derived mesenchymal stem cells. Chromosome Res. 2009; 17:1025–1039.CrossrefMedlineGoogle Scholar20. Jeong JO, Han JW, Kim JM, Cho HJ, Park C, Lee N, Kim DW, Yoon YS. Malignant tumor formation after transplantation of short-term cultured bone marrow mesenchymal stem cells in experimental myocardial infarction and diabetic neuropathy. Circ Res. 2011; 108:1340–1347.LinkGoogle Scholar21. Butany J, Leong SW, Carmichael K, Komeda M. A 30-year analysis of cardiac neoplasms at autopsy. Can J Cardiol. 2005; 21:675–680.MedlineGoogle Scholar22. Rangarajan A, Hong SJ, Gifford A, Weinberg RA. Species- and cell type-specific requirements for cellular transformation. Cancer Cell. 2004; 6:171–183.CrossrefMedlineGoogle Scholar23. Rangarajan A, Weinberg RA. Opinion: comparative biology of mouse versus human cells: modelling human cancer in mice. Nat Rev Cancer. 2003; 3:952–959.CrossrefMedlineGoogle Scholar24. Karnoub AE, Dash AB, Vo AP, Sullivan A, Brooks MW, Bell GW, Richardson AL, Polyak K, Tubo R, Weinberg RA. Mesenchymal stem cells within tumour stroma promote breast cancer metastasis. Nature. 2007; 449:557–563.CrossrefMedlineGoogle Scholar25. Calo E, Quintero-Estades JA, Danielian PS, Nedelcu S, Berman SD, Lees JA. Rb regulates fate choice and lineage commitment in vivo. Nature. 2010; 466:1110–1114.CrossrefMedlineGoogle Scholar26. Li N, Yang R, Zhang W, Dorfman H, Rao P, Gorlick R. Genetically transforming human mesenchymal stem cells to sarcomas: changes in cellular phenotype and multilineage differentiation potential. Cancer. 2009; 115:4795–4806.CrossrefMedlineGoogle Scholar27. Nagaya N, Kangawa K, Itoh T, Iwase T, Murakami S, Miyahara Y, Fujii T, Uematsu M, Ohgushi H, Yamagishi M, Tokudome T, Mori H, Miyatake K, Kitamura S. Transplantation of mesenchymal stem cells improves cardiac function in a rat model of dilated cardiomyopathy. Circulation. 2005; 112:1128–1135.LinkGoogle Scholar28. Mangi AA, Noiseux N, Kong D, He H, Rezvani M, Ingwall JS, Dzau VJ. Mesenchymal stem cells modified with Akt prevent remodeling and restore performance of infarcted hearts. Nat Med. 2003; 9:1195–1201.CrossrefMedlineGoogle Scholar29. Nishiyama N, Miyoshi S, Hida N, Uyama T, Okamoto K, Ikegami Y, Miyado K, Segawa K, Terai M, Sakamoto M, Ogawa S, Umezawa A. The significant cardiomyogenic potential of human umbilical cord blood-derived mesenchymal stem cells in vitro. Stem Cells. 2007; 25:2017–2024.CrossrefMedlineGoogle Scholar30. Toma C, Pittenger MF, Cahill KS, Byrne BJ, Kessler PD. Human mesenchymal stem cells differentiate to a cardiomyocyte phenotype in the adult murine heart. Circulation. 2002; 105:93–98.LinkGoogle Scholar31. Antonitsis P, Ioannidou-Papagiannaki E, Kaidoglou A, Charokopos N, Kalogeridis A, Kouzi-Koliakou K, Kyriakopoulou I, Klonizakis I, Papakonstantinou C. Cardiomyogenic potential of human adult bone marrow mesenchymal stem cells in vitro. Thorac Cardiovasc Surg. 2008; 56:77–82.CrossrefMedlineGoogle Scholar32. Chou SH, Kuo TK, Liu M, Lee OK. In utero transplantation of human bone marrow–derived multipotent mesenchymal stem cells in mice. J Orthop Res. 2006; 24:301–312.CrossrefMedlineGoogle Scholar33. Dai W, Hale SL, Martin BJ, Kuang JQ, Dow JS, Wold LE, Kloner RA. Allogeneic mesenchymal stem cell transplantation in postinfarcted rat myocardium: short- and long-term effects. Circulation. 2005; 112:214–223.LinkGoogle Scholar34. Zhang D, Fan GC, Zhou X, Zhao T, Pasha Z, Xu M, Zhu Y, Ashraf M, Wang Y. Over-expression of CXCR4 on mesenchymal stem cells augments myoangiogenesis in the infarcted myocardium. J Mol Cell Cardiol. 2008; 44:281–292.CrossrefMedlineGoogle Scholar35. Gnecchi M, He H, Liang OD, Melo LG, Morello F, Mu H, Noiseux N, Zhang L, Pratt RE, Ingwall JS, Dzau VJ. Paracrine action accounts for marked protection of ischemic heart by Akt-modified mesenchymal stem cells. Nat Med. 2005; 11:367–368.CrossrefMedlineGoogle Scholar36. Mirotsou M, Zhang Z, Deb A, Zhang L, Gnecchi M, Noiseux N, Mu H, Pachori A, Dzau V. Secreted frizzled related protein 2 (Sfrp2) is the key Akt-mesenchymal stem cell–released paracrine factor mediating myocardial survival and repair. Proc Natl Acad Sci U S A. 2007; 104:1643–1648.CrossrefMedlineGoogle Scholar37. Loffredo FS, Steinhauser ML, Gannon J, Lee RT. Bone marrow–derived cell therapy stimulates endogenous cardiomyocyte progenitors and promotes cardiac repair. Cell Stem Cell. 2011; 8:389–398.CrossrefMedlineGoogle Scholar38. Pijnappels DA, Schalij MJ, Ramkisoensing AA, van TJ, de Vries AA, van der Laarse A, Ypey DL, Atsma DE. Forced alignment of mesenchymal stem cells undergoing cardiomyogenic differentiation affects functional integration with cardiomyocyte cultures. Circ Res. 2008; 103:167–176.LinkGoogle Scholar39. Javazon EH, Colter DC, Schwarz EJ, Prockop DJ. Rat marrow stromal cells are more sensitive to plating density and expand more rapidly from single-cell-derived colonies than human marrow stromal cells. Stem Cells. 2001; 19:219–225.CrossrefMedlineGoogle Scholar40. Peister A, Mellad JA, Larson BL, Hall BM, Gibson LF, Prockop DJ. Adult stem cells from bone marrow (MSCs) isolated from different strains of inbred mice vary in surface epitopes, rates of proliferation, and differentiation potential. Blood. 2004; 103:1662–1668.CrossrefMedlineGoogle Scholar41. Phinney DG, Kopen G, Isaacson RL, Prockop DJ. Plastic adherent stromal cells from the bone marrow of commonly used strains of inbred mice: variations in yield, growth, and differentiation. J Cell Biochem. 1999; 72:570–585.CrossrefMedlineGoogle Scholar42. Rubio D, Garcia-Castro J, Martin MC, de la FR, Cigudosa JC, Lloyd AC, Bernad A. Spontaneous human adult stem cell transformation. Cancer Res. 2005; 65:3035–3039.CrossrefMedlineGoogle Scholar43. de la Fuente R, Bernad A, Garcia-Castro J, Martin MC, Cigudosa JC. Retraction: spontaneous human adult stem cell transformation. Cancer Res. 2010; 70:6682.CrossrefMedlineGoogle Scholar44. Torsvik A, Rosland GV, Svendsen A, Molven A, Immervoll H, McCormack E, Lonning PE, Primon M, Sobala E, Tonn JC, Goldbrunner R, Schichor C, Mysliwietz J, Lah TT, Motaln H, Knappskog S, Bjerkvig R. Spontaneous malignant transformation of human mesenchymal stem cells reflects cross-contamination: putting the research field on track [letter]. Cancer Res. 2010; 70:6393–6396.CrossrefMedlineGoogle Scholar45. Rosland GV, Svendsen A, Torsvik A, Sobala E, McCormack E, Immervoll H, Mysliwietz J, Tonn JC, Goldbrunner R, Lonning PE, Bjerkvig R, Schichor C. Long-term cultures of bone marrow–derived human mesenchymal stem cells frequently undergo spontaneous malignant transformation. Cancer Res. 2009; 69:5331–5339.CrossrefMedlineGoogle Scholar46. Wang Y, Huso DL, Harrington J, Kellner J, Jeong DK, Turney J, McNiece IK. Outgrowth of a transformed cell population derived from normal human BM mesenchymal stem cell culture. Cytoth
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