The Tumorigenicity of Mouse Embryonic Stem Cells and In Vitro Differentiated Neuronal Cells Is Controlled by the Recipients' Immune Response

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

Effects of histocompatibility and host immune responses on the tumorigenicity of pluripotent stem cells

Pluripotent stem cells hold great promises for regenerative medicine. They might become useful as a universal source for a battery of new cell replacement therapies. Among the major concerns for the clinical application of stem cell-derived grafts are the risks of immune rejection and tumor formation. Pluripotency and tumorigenicity are closely linked features of pluripotent stem cells. However, the capacity to form teratomas or other tumors is not sufficiently described by inherited features of a stem cell line or a stem cell-derived graft. The tumorigenicity always depends on the inability of the recipient to reject the tumorigenic cells. This review summarizes recent data on the tumorigenicity of pluripotent stem cells in immunodeficient, syngeneic, allogeneic, and xenogeneic hosts. The effects of immunosuppressive treatment and cell differentiation are discussed. Different immune effector mechanisms appear to be involved in the rejection of undifferentiated and differentiated cell populations. Elements of the innate immune system, such as natural killer cells and the complement system, which are active also in syngeneic recipients, appear to preferentially reject undifferentiated cells. This effect could reduce the risk of tumor formation in immunocompetent recipients. Cell differentiation apparently increases susceptibility to rejection by the adaptive immune system in allogeneic hosts. The current data suggest that the immune system of the recipient has a major impact on the outcome of pluripotent stem cell transplantation, whether it is rejection, engraftment, or tumor development. This has to be considered when the results of experimental transplantation models are interpreted and even more when translation into clinics is planned

Autoradiographic localization of [3H]muscimol binding sites in rat stomach: evidence for mucosal GABAA receptors.

The distribution in the rat stomach of specific [3H]muscimol binding sites, which show characteristics of GABAA receptors, was examined by light microscopic autoradiography. Silver grains representing specific binding were present both in the antrum and body, with highest densities in the muscle layers. A small fraction of the binding was confined to gland cells of the mucosa in the gastric body, rather than in the antrum. The label was not specifically concentrated at the myenteric ganglia. These findings, along with earlier data, suggests that the local GABA content may regulate not only the contractility, but also the secretory functions of the stomach via gastric GABAA receptors

Autoradiographic localization of the GABAA receptor agonist [3H]-muscimol within rat kidney

By the use of combined radioreceptor binding and autoradiographic techniques, the pharmacological characteristics of (3H)-muscimol binding and the localization of the label were studied. (3H)-Muscimol was bound by sections of rat kidney in a manner consistent with the existence of specific gamma-aminobutyric acid 'A' (GABAA) receptors with KD and Bmax values of 23.7 nmol/l and 1.15 pmol/mg tissue, respectively. (3H)-Muscimol was bound by convoluted tubules of the renal cortex and by the collecting tubules. Our findings demonstrating the existence of recognition sites for the GABAA receptor agonist muscimol in the kidney suggest that GABA has a role in renal function

Autoradiographic localization of the GABAA receptor agonist [3H]-muscimol within rat kidney

By the use of combined radioreceptor binding and autoradiographic techniques, the pharmacological characteristics of (3H)-muscimol binding and the localization of the label were studied. (3H)-Muscimol was bound by sections of rat kidney in a manner consistent with the existence of specific gamma-aminobutyric acid 'A' (GABAA) receptors with KD and Bmax values of 23.7 nmol/l and 1.15 pmol/mg tissue, respectively. (3H)-Muscimol was bound by convoluted tubules of the renal cortex and by the collecting tubules. Our findings demonstrating the existence of recognition sites for the GABAA receptor agonist muscimol in the kidney suggest that GABA has a role in renal function

Stem cells for the treatment of stroke: malignant transformation of homologous transplants

Copyright 2002 Springer-Verlag Berlin Heidelber