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Tumorigenicity Evaluation of Umbilical Cord Blood-derived Mesenchymal Stem Cells
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  • Journal title : Toxicological Research
  • Volume 32, Issue 3,  2016, pp.251-258
  • Publisher : The Korean Society of Toxicology
  • DOI : 10.5487/TR.2016.32.3.251
 Title & Authors
Tumorigenicity Evaluation of Umbilical Cord Blood-derived Mesenchymal Stem Cells
Park, Sang-Jin; Kim, Hyun-Jung; Kim, Woojin; Kim, Ok-Sun; Lee, Sunyeong; Han, Su-Yeon; Jeong, Eun Ju; Park, Hyun-shin; Kim, Hea-Won; Moon, Kyoung-Sik;
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Mesenchymal stem cells (MSCs) have been identified in multiple types of tissue and exhibit characteristic self-renewal and multi-lineage differentiation abilities. However, the possibility of oncogenic transformation after transplantation is concerning. In this study, we investigated the tumorigenic potential of umbilical cord blood-derived MSCs (hUCB-MSCs) relative to MRC-5 and HeLa cells (negative and positive controls, respectively) both in vitro and in vivo. To evaluate tumorigenicity in vitro, anchorage-independent growth was assessed using the soft agar colony formation assay. hUCB-MSCs and MRC-5 cells formed few colonies, while HeLa cells formed a greater number of larger colonies, indicating that hUCB-MSCs and MRC-5 cells do not have anchorage-independent proliferation potential. To detect tumorigenicity in vivo, hUCB-MSCs were implanted as a single subcutaneous injection into BALB/c-nu mice. No tumor formation was observed in mice transplanted with hUCB-MSCs or MRC-5 cells based on macro- and microscopic examinations; however, all mice transplanted with HeLa cells developed tumors that stained positive for a human gene according to immunohistochemical analysis. In conclusion, hUCB-MSCs do not exhibit tumorigenic potential based on in vitro and in vivo assays under our experimental conditions, providing further evidence of their safety for clinical applications.
Tumorigenicity;Mesenchymal stem cells;Immunohistochemistry;Soft agar assay;
 Cited by
Double-edged sword of mesenchymal stem cells: Cancer-promoting versus therapeutic potential, Cancer Science, 2017, 108, 10, 1939  crossref(new windwow)
Lee, O.K., Kuo, T.K., Chen, W.M., Lee, K.D., Hsieh, S.L. and Chen. T.H. (2004) Isolation of multipotent mesenchymal stem cells from umbilical cord blood. Blood, 103, 1669-1675. crossref(new window)

Bartholomew, A., Sturgeon, C., Siatskas, M., Ferrer, K., McIntosh, K., Patil, S., Hardy, W., Devine, S., Ucker, D., Deans, R., Moseley, A. and Hoffman, R. (2002) Mesenchymal stem cells suppress lymphocyte proliferation in vitro and prolong skin graft survival in vivo. Exp. Hematol., 30, 42-48. crossref(new window)

Stamm, C., Westphal, B., Kleine, H.D., Petzsch, M., Kittner, C., Klinge, H., Schumichen, C., Nienaber, C.A., Freund, M. and Steinhoff, G. (2003) Autologous bone-marrow stem-cell transplantation for myocardial regeneration. Lancet, 361, 45-46. crossref(new window)

Barry, F.P. and Murphy, J.M. (2004) Mesenchymal stem cells: clinical applications and biological characterization. Int. J. Biochem. Cell Biol., 36, 568-584. crossref(new window)

Xu, W., Zhang, X., Qian, H., Zhu, W., Sun, X., Hu, J., Zhou, H. and Chen, Y. (2004) Mesenchymal stem cells from adult human bone marrow differentiate into a cardiomyocyte phenotype in vitro. Exp. Biol. Med. (Maywood), 229, 623-631. crossref(new window)

Kassem, M. and Abdallah, B.M. (2008) Human bone-marrow-derived mesenchymal stem cells: biological characteristics and potential role in therapy of degenerative diseases. Cell Tissue Res., 331, 157-163. crossref(new window)

Devine, S.M., Cobbs, C., Jennings, M., Bartholomew, A. and Hoffman, R. (2003) Mesenchymal stem cells distribute to a wide range of tissues following systemic infusion into nonhuman primates. Blood, 101, 2999-3001. crossref(new window)

Houghton, J., Stoicov, C., Nomura, S., Rogers, A.B., Carlson, J., Li, H., Cai, X., Fox, J.G., Goldenring, J.R. and Wang, T.C. (2004) Gastric cancer originating from bone marrow-derived cells. Science, 306, 1568-1571. crossref(new window)

Goldring, C.E., Duffy, P.A., Benvenisty, N., Andrews, P.W., Ben-David, U., Eakins, R., French, N., Hanley, N.A., Kelly, L., Kitteringham, N.R., Kurth, J., Ladenheim, D., Laverty, H., McBlane, J., Narayanan, G., Patel, S., Reinhardt, J., Rossi, A., Sharpe, M. and Park, B.K. (2011) Assessing the safety of stem cell therapeutics. Cell Stem Cell, 8, 618-628. crossref(new window)

Yu, K.R., Lee, J.Y., Kim, H.S., Hong, I.S., Choi, S.W., Seo, Y., Kang, I., Kim, J.J., Lee, B.C., Lee, S., Kurtz, A., Seo, K.W. and Kang, K.S. (2014) A p38 MAPK-mediated alteration of COX-2/PGE2 regulates immunomodulatory properties in human mesenchymal stem cell aging. PLoS ONE, 9, e102426. crossref(new window)

Kim, H.S., Shin, T.H., Lee, B.C., Yu, K.R., Seo, Y., Lee, S., Seo, M.S., Hong, I.S., Choi, S.W., Seo, K.W., Nunez, G., Park, J.H. and Kang, K.S. (2013) Human umbilical cord blood mesenchymal stem cells reduce colitis in mice by activating NOD2 signaling to COX2. Gastroenterology, 145, 1392-1403. crossref(new window)

Kawamata, S., Kanemura, H., Sakai, N., Takahashi, M. and Go, M.J. (2015) Design of a tumorigenicity test for induced pluripotent stem cell (iPSC)-derived cell products. J. Clin. Med., 4, 159-171. crossref(new window)

Chuah, M.K., Damme, A.V., Zwinnen, H., Goovaerts, I., Vanslembrouck, V., Collen, D. and Vandendriessche, T. (2000) Long-term persistence of human bone marrow stromal cells transduced with factor VIII-retroviral vectors and transient production of therapeutic levels of human factor VIII in nonmyeloablated immunodeficient mice. Hum. Gene Ther., 11, 729-738. crossref(new window)

Campagnoli, C., Bellantuono, I., Kumar, S., Fairbairn, L.J., Roberts, I. and Fisk, N.M. (2002) High transduction efficiency of circulating first trimester fetal mesenchymal stem cells: potential targets for in utero ex vivo gene therapy. BJOG, 109, 952-954. crossref(new window)

Fouillard, L., Bensidhoum, M., Bories, D., Bonte, H., Lopez, M., Moseley, A.M., Smith, A., Lesage, S., Beaujean, F., Thierry, D., Gourmelon, P., Najman, A. and Gorin, N.C. (2003) Engraftment of allogeneic mesenchymal stem cells in the bone marrow of a patient with severe idiopathic aplastic anemia improves stroma. Leukemia, 17, 474-476. crossref(new window)

Amado, L.C., Saliaris, A.P., Schulei, K.H., Marcus, S.J., Xie, J.S., Cattaneo, S., Durand, D.J., Fitton, T., Kuang, J.Q., Stewart, G., Lehrke, S., Baumgartner, W.W., Bradley, J.M., Heldman, A.W. and Hare, J.M. (2005) Cardiac repair with intramyocardial injection of allogeneic mesenchymal stem cells after myocardial infarction. Proc. Natl. Acad. Sci. U.S.A., 102, 11474-11479. crossref(new window)

Djouad, F., Plence, P., Bony, C., Tropel, P., Apparailly, F., Sany, J., Noel, D. and Jorgensen, C. (2003) Immunosuppressive effect of mesenchymal stem cells favors tumor growth in allogeneic animals. Blood, 102, 3837-3844. crossref(new window)

Sato, T., Sakai, T., Noguchi, Y., Takita, M., Hirakawa, S. and Ito, A. (2004) Tumor-stromal cell contact promotes invasion of human uterine cervical carcinoma cells by augmenting the expression and activation of stromal matrix metalloproteinases. Gynecol. Oncol., 92, 47-56. crossref(new window)

Zhu, W., Xu, W., Jiang, R., Qian, H., Chen, M., Hu, J., Cao, W., Han, C. and Chen, Y. (2006) Mesenchymal stem cells derived from bone marrow favor tumor cell growth in vivo. Exp. Mol. Pathol., 80, 267-274. crossref(new window)

Tolar, J., Nauta, A.J., Osborn, M.J., Panoskaltsis Mortari, A., McElmurry, R.T., Bell, S., Xia, L., Zhou, N., Riddle, M., Schroeder, T.M., Westendorf, J.J., McIvor, R.S., Hogendoorn, P.C., Szuhai, K., Oseth, L., Hirsch, B., Yant, S.R., Kay, M.A., Peister, A., Prockop, D.J., Fibbe, W.E. and Blazar, B.R. (2007) Sarcoma derived from cultured mesenchymal stem cells. Stem Cells, 25, 371-379. crossref(new window)

Amariglio, N., Hirshberg, A., Scheithauer, B.W., Cohen, Y., Loewenthal, R., Trakhtenbrot, L., Paz, N., Koren-Michowitz, M., Waldman, D., Leider-Trejo, L., Toren, A., Constantini, S. and Rechavi, G. (2009) Donor-derived brain tumor following neural stem cell transplantation in an ataxia telangiectasia patient. PLoS Med., 6, e1000029. crossref(new window)

Shin, S.I., Freedman, V.H., Risser, R. and Pollack, R. (1975) Tumorigenicity of virus-transformed cells in nude mice is correlated specifically with anchorage independent growth in vitro. Proc. Natl. Acad. Sci. U.S.A., 72, 4435-4439. crossref(new window)

Sabapathy, V., Ravi, V., Srivastava, V., Srivastava, A. and Kumar, S. (2012) Long-term cultured human term placentaderived mesenchymal stem cells of maternal origin displays plasticity. Stem Cells Int., 2012, 174328.

Sabapathy, V., Sundaram, B., V.M.S., Mankuzhy, P. and Kumar, S. (2014) Human Wharton's Jelly mesenchymal stem cells plasticity augments scar-free skin wound healing with hair growth. PLoS ONE, 9, e93726. crossref(new window)

Ra, J.C., Shin, I.S., Kim, S.H., Kang, S.K., Kang, B.C., Lee, H.Y., Kim, Y.J., Jo, J.Y., Yoon, E.J., Choi, H.J. and Kwon, E. (2011) Safety of intravenous infusion of human adipose tissue-derived mesenchymal stem cells in animals and humans. Stem Cells Dev., 20, 1297-1308. crossref(new window)

Lopez-Iglesias, P., Blazquez-Martinez, A., Fernandez-Delgado, J., Regadera, J., Nistal, M. and Miguel, M.P. (2011) Short and long term fate of human AMSC subcutaneously injected in mice. World J. Stem Cells, 3, 53-62. crossref(new window)