BACKGROUND: The recent success in the derivation of differentiated cell types from stem cells has raised prospects for the application of regenerative cell therapy. In particular, embryonic stem cells are attractive sources for cell transplantation, due to their immortality and rapid growth. These cells, however, also possess tumorigenic properties, which raises serious safety concerns and makes biosafety testing mandatory. Our goal was to establish a highly sensitive animal model for testing the proliferative potential of stem-cell grafts. METHODS: BALB/c nude mice received cell grafts of non-neoplastic MRC-5 cells containing defined numbers of mouse embryonic stem cells. We either injected 1 million viable cells into the kidney capsule, or mixed 2 million cells with Matrigel for s.c. transplantation. To analyze the possible impact of an intact immune response on tumor development, we also transplanted the cells into immunocompetent mice. Animals were sacrificed when the tumors became >1 cm and were analyzed in detail. RESULTS: The nude mouse model reproducibly allowed detection of 20 tumorigenic cells, and even as few as 2 ES cells were found to form teratoma. Interestingly, the administration of cell grafts at two different application sites resulted in different growth kinetics and tumor phenotypes. The highest level of sensitivity (100% detection of 20 tumorigenic ES cells) was achieved by s.c. injection of cells mixed with Matrigel. The influence of the immune system on tumor-cell development was demonstrated by a higher tumor rate of transplants in immunodeficient nude mice compared with immunocompetent mice. DISCUSSION: We have established a reliable animal model for routine assessment of the biosafety profile of stem-cell-derived cell transplants. This model will facilitate the generation of homogenous non-tumorigenic cell populations, and will help to integrate standardized safety systems into the application of stem-cell-derived grafts for clinical purposes.
BACKGROUND: The recent success in the derivation of differentiated cell types from stem cells has raised prospects for the application of regenerative cell therapy. In particular, embryonic stem cells are attractive sources for cell transplantation, due to their immortality and rapid growth. These cells, however, also possess tumorigenic properties, which raises serious safety concerns and makes biosafety testing mandatory. Our goal was to establish a highly sensitive animal model for testing the proliferative potential of stem-cell grafts. METHODS: BALB/c nude mice received cell grafts of non-neoplastic MRC-5 cells containing defined numbers of mouse embryonic stem cells. We either injected 1 million viable cells into the kidney capsule, or mixed 2 million cells with Matrigel for s.c. transplantation. To analyze the possible impact of an intact immune response on tumor development, we also transplanted the cells into immunocompetent mice. Animals were sacrificed when the tumors became >1 cm and were analyzed in detail. RESULTS: The nude mouse model reproducibly allowed detection of 20 tumorigenic cells, and even as few as 2 ES cells were found to form teratoma. Interestingly, the administration of cell grafts at two different application sites resulted in different growth kinetics and tumor phenotypes. The highest level of sensitivity (100% detection of 20 tumorigenic ES cells) was achieved by s.c. injection of cells mixed with Matrigel. The influence of the immune system on tumor-cell development was demonstrated by a higher tumor rate of transplants in immunodeficientnude mice compared with immunocompetent mice. DISCUSSION: We have established a reliable animal model for routine assessment of the biosafety profile of stem-cell-derived cell transplants. This model will facilitate the generation of homogenous non-tumorigenic cell populations, and will help to integrate standardized safety systems into the application of stem-cell-derived grafts for clinical purposes.
Authors: Alejandro De Los Angeles; Francesco Ferrari; Yuko Fujiwara; Ronald Mathieu; Soohyun Lee; Semin Lee; Ho-Chou Tu; Samantha Ross; Stephanie Chou; Minh Nguyen; Zhaoting Wu; Thorold W Theunissen; Benjamin E Powell; Sumeth Imsoonthornruksa; Jiekai Chen; Marti Borkent; Vladislav Krupalnik; Ernesto Lujan; Marius Wernig; Jacob H Hanna; Konrad Hochedlinger; Duanqing Pei; Rudolf Jaenisch; Hongkui Deng; Stuart H Orkin; Peter J Park; George Q Daley Journal: Nature Date: 2015-09-24 Impact factor: 49.962
Authors: Erin M Kropp; Bryndon J Oleson; Katarzyna A Broniowska; Subarna Bhattacharya; Alexandra C Chadwick; Anne R Diers; Qinghui Hu; Daisy Sahoo; Neil Hogg; Kenneth R Boheler; John A Corbett; Rebekah L Gundry Journal: Stem Cells Transl Med Date: 2015-04-01 Impact factor: 6.940
Authors: Natalia Vapniarsky; Boaz Arzi; Jerry C Hu; Jan A Nolta; Kyriacos A Athanasiou Journal: Stem Cells Transl Med Date: 2015-08-07 Impact factor: 6.940