Development of Experimental Tumors Formed by Mouse and Human Embryonic Stem and Teratocarcinoma Cells after Subcutaneous and Intraperitoneal Transplantations into Immunodeficient and Immunocompetent Mice

Abstract

Pluripotent stem cells represent an attractive cell source for regenerative medicine. However, the risk of teratoma formation after transplantation restricts their clinical application. Therefore, to adequately evaluate the potential risk of tumorigenicity after cell transplantation into human tissues, effective animal transplantation assays need to be developed. We performed a multiparameter (cell number, transplantation site, cell type, host) comparative analysis of the efficiency of tumor development after transplantation of mouse and human embryonic stem (ES) cells and their malignant counterparts, teratocarcinoma (EC) cells, into animal recipients and revealed several key correlations. We found that the efficiency of tumor growth was higher after intraperitoneal than after subcutaneous transplantations of all cell lines studied. The minimal cell numbers sufficient for tumor growth in immunodeficient nude mice were 100-fold lower for intraperitoneal than for subcutaneous transplantations of mouse and human ES cells (10(3) vs. 10(5) and 10(4) vs. 10(6), respectively). Moreover, mouse ES and EC cells formed tumors in immunodeficient and immunocompetent mice more effectively than human ES and EC cells. After intraperitoneal transplantation of 10(3), 10(4), and 10(5) mouse ES cells, teratomas developed in 83%, 100%, and 100% of nude mice, whereas after human ES cell transplantation, teratomas developed in 0%, 17%, and 60%, respectively. In addition, malignant mouse and human EC cells initiated tumor growth after intraperitoneal transplantation significantly faster and more effectively than ES cells. Mouse and human ES cells formed different types of teratomas containing derivatives of three germ layers but different numbers of undifferentiated cells. ES cell-like sublines with differentiation potential similar to the parental cell line were recloned only from mouse, but not from human, ES cell teratomas. These findings provide new information about the possibility and efficiency of tumor growth after transplantation of pluripotent stem cells. This information allows one to predict and possibly prevent the possible risks of tumorigenicity that could arise from stem cell therapeutics.