Abstract
Embryonic stem (ES) cells have the potential to differentiate into all cell types and are considered as a valuable source of cells for transplantation therapies. A critical issue, however, is the risk of teratoma formation after transplantation. The effect of the immune response on the tumorigenicity of transplanted cells is poorly understood. We have systematically compared the tumorigenicity of mouse ES cells and in vitro differentiated neuronal cells in various recipients. Subcutaneous injection of 1×106 ES or differentiated cells into syngeneic or allogeneic immunodeficient mice resulted in teratomas in about 95% of the recipients. Both cell types did not give rise to tumors in immunocompetent allogeneic mice or xenogeneic rats. However, in 61% of cyclosporine A-treated rats teratomas developed after injection of differentiated cells. Undifferentiated ES cells did not give rise to tumors in these rats. ES cells turned out to be highly susceptible to killing by rat natural killer (NK) cells due to the expression of ligands of the activating NK receptor NKG2D on ES cells. These ligands were down-regulated on differentiated cells. The activity of NK cells which is not suppressed by cyclosporine A might contribute to the prevention of teratomas after injection of ES cells but not after inoculation of differentiated cells. These findings clearly point to the importance of the immune response in this process. Interestingly, the differentiated cells must contain a tumorigenic cell population that is not present among ES cells and which might be resistant to NK cell-mediated killing.
Highlights
Embryonic stem (ES) cells are a potential source of cells and tissues for transplantation in regenerative medicine
E. g., that undifferentiated mouse ES cells can develop into functional dopaminergic neurons after intrastriatal transplantation in a rat model of Parkinson’s disease but teratomas occurred in about 20% of the recipients which had been treated with cyclosporine A (CsA) for immunosuppression [1]
When these in vitro differentiated neuronal cells were transplanted into CsA-treated recipients, tyrosine hydroxylase (TH)-positive neurites were present in the grafts suggesting a better integration of transplanted cells, teratomas occurred in 2 of 15 animals [4]
Summary
Embryonic stem (ES) cells are a potential source of cells and tissues for transplantation in regenerative medicine. Transplantation of dopaminergic neurons differentiated in vitro from ES cells improved amphetamine-induced rotational behavior in the unilaterally 6-hydroxydopamine (6-OHDA)-lesioned rat model for Parkinson’s disease [2] These rats which were continuously treated with CsA did not develop teratomas [2]. Despite the behavioral changes of the transplanted animals, the grafted cells remained in compact deposits surrounded by glia cells without functional integration into the host tissue [3], which is postulated for an optimal long-term survival of grafts When these in vitro differentiated neuronal cells were transplanted into CsA-treated recipients, tyrosine hydroxylase (TH)-positive neurites were present in the grafts suggesting a better integration of transplanted cells, teratomas occurred in 2 of 15 animals [4]. In one study a higher prevalence of teratomas was observed after intracerebral trans-
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