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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
Circ Res. Author manuscript; available in PMC 2012 July 6.
Published in final edited form as:
PMCID: PMC3390911

What is the oncologic risk of stem cell treatment for heart disease?

Every 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 MSCs-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 inhered limitations to 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 appears more effective than bone marrow mononuclear cells.16 Importantly, large animal work provides a phenotyping opportunity not available in rodents, and rigorous cardiac magnetic resonance imaging (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.11

Chromosomal instability and the risk of neoplastic transformation

In 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 al17, Breitbach et al18, Foudah et al19 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 conclude 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 heart21, the aggressiveness and size of the tumors that Jeong et al. describe in ~33% of the MSCs-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 vs human cells is described. Rangarajan et al.22 demonstrated that whereas perturbation of 6 signaling pathways in human fibroblasts was required for tumorigenic transformation, mouse fibroblasts required only two (p53 and Raf). Considering that a typical random mutation rate is 10×-6- 10×-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 compared to 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 sarcomas25, 26, and therefore the possibility that human MSCs could also undergo chromosomal transformations that promote growth and/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 employed to rigorously gauge the risk of any adverse effect of a new therapeutic modality.

Efficacy of rodent vs. human MSCs

A 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 a direct and indirect manner2, 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, since 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 abundantly20, 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 lab-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 4-5 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 4-6 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 HT1080.44

In 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 MSCs 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 co-workers generated more than 100 human MSCs lines, of which 1 yielded a transformed population. Of crucial importance, however, this transformed cell was present in the original bone marrow sample and expanded with time in culture, suggesting it was actuality 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.46

Together, 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 therapy

How 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 employed whole body autopsies to establish that MSCs-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 oncologic risk due to underlying co-morbidities such as HIV, hepatitis, hematologic disorders or history of malignancy have been excluded by trial design.12, 15

Results of preclinical and clinical studies

Careful 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 al.16) By studying more than 150 swine in our lab 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 magnetic resonance imaging and whole body histologic analysis. In these studies, tumors (cardiac or otherwise) or ectopic tissue formation have not been observed. These findings contributed to the design and conduct four 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 for tumor outgrowth have ever been reported, substantiating the concept that the risk for primary cancer development following bone marrow-based cellular cardiomyoplasty is minimal.


Accumulating clinical and preclinical trials are adding to the database supporting the idea that human cell therapy with MSCs 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 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.

Sources of Funding

This 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's AG025017, HL065455, and HL094849.

Non-standard abbreviations and acronyms

Mesenchymal stem cells
rodent mesenchymal stem cells
human mesenchymal stem cells
cardiac magnetic resonance imaging
Computed Tomography
Good manufacturing practice


Disclosures The authors have nothing to disclose.

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1. 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. [PubMed]
2. 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. [PubMed]
3. Zhou Y, Wang S, Yu Z, Hoyt RF, Jr., 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. [PMC free article] [PubMed]
4. 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. [PubMed]
5. 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. [PubMed]
6. 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. [PubMed]
7. 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. [PubMed]
8. 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. [PubMed]
9. 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. [PubMed]
10. 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. [PMC free article] [PubMed]
11. 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 [PMC free article] [PubMed]
12. Hare JM, Traverse JH, Henry TD, Dib N, Strumpf RK, Schulman SP, Gerstenblith G, DeMaria AN, Denktas AE, Gammon RS, Hermiller JB, Jr., 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. [PubMed]
13. 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. [PubMed]
14. 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. [PubMed]
15. 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. [PMC free article] [PubMed]
16. 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 [PubMed]
17. 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. [PubMed]
18. 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. [PubMed]
19. 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. [PMC free article] [PubMed]
20. 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:XXX–XXX. [PMC free article] [PubMed]
21. Butany J, Leong SW, Carmichael K, Komeda M. A 30-year analysis of cardiac neoplasms at autopsy. Can J Cardiol. 2005;21:675–680. [PubMed]
22. Rangarajan A, Hong SJ, Gifford A, Weinberg RA. Species- and cell type-specific requirements for cellular transformation. Cancer Cell. 2004;6:171–183. [PubMed]
23. Rangarajan A, Weinberg RA. Opinion: Comparative biology of mouse versus human cells: modelling human cancer in mice. Nat Rev Cancer. 2003;3:952–959. [PubMed]
24. 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. [PubMed]
25. 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. [PMC free article] [PubMed]
26. 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. [PMC free article] [PubMed]
27. 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. [PubMed]
28. 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. [PubMed]
29. 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. [PubMed]
30. 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. [PubMed]
31. 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. [PubMed]
32. 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. [PubMed]
33. 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. [PubMed]
34. 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. [PMC free article] [PubMed]
35. 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. [PubMed]
36. 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. [PubMed]
37. 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. [PubMed]
38. 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. [PubMed]
39. 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. [PubMed]
40. 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. [PubMed]
41. 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. [PubMed]
42. 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. [PubMed]
43. 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. [PubMed]
44. 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. [PubMed]
45. 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. [PubMed]
46. 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. Cytotherapy. 2005;7:509–519. [PubMed]
47. Kraitchman DL, Heldman AW, Atalar E, Amado LC, Martin BJ, Pittenger MF, Hare JM, Bulte JW. In vivo magnetic resonance imaging of mesenchymal stem cells in myocardial infarction. Circulation. 2003;107:2290–2293. [PubMed]