Telomerase Activity, mTert Gene Expression and the Telomere Length in Mouse Mesenchymal Stem Cells in the Late Period after γ- and γ,n-Irradiation and in Tumors Developed from These Cells

In proliferating normal and tumor cells, the telomere length (TL) is maintained by high telomerase activity (TA). In the absence of TA the TL maintenance involves a mechanism of alternative lengthening of telomeres (ALT). In order to investigate the role of TA or ALT in maintaining TL we studied the level of TA, mTert expression, and TL in cultivated normal and transformed by gamma- and gamma,n-irradiation mesenchymal stem cells (MSCs) from mouse bone marrow, as well as in sarcomas that developed after transplantation of these cells into syngeneic mice, and in fibrosarcoma cell lines obtained from these tumors. During prolonged cultivation of normal and transformed under the influence of gamma- (1 Gy and 6 Gy) and gamma,n-irradiation (0.05 Gy, 0.5 Gy, and 2 Gy) MSCs from mouse bone marrow, a decrease in TA was detected in the irradiated cells. Even a deeper decrease in TA was found in sarcomas developed after administration of transformed MSCs to syngeneic mice and in fibrosarcoma cell lines isolated from these tumors in which TA was either absent or was found to be at a very low level. In three of the four lines obtained TL was two times lower than in the initial MSCs. With absent or low TA and reduced TL, the cells of all the obtained fibrosarcoma lines successfully proliferated without signs of altered survival. The mechanism of telomere maintainance in fibrosarcoma cell lines in the absence of TA needs further investigation and it can be associated with involvement of the ALT pathway. The detected decrease or the absence of TA in irradiation-transformed MSCs with preserved or even an increased in the telomerase gene expression may be associated with the formation of inactive splice variants, and requires further study. The obtained lines of transformed MSCs and fibrosarcomas with and without TA can be a useful model for studying the efficacy of TA and ALT inhibitors in vitro and in vivo.