Preservation Versus Elongation Of Telomere Length In Cloned Animals

The expanded replicative potential demonstrated by serial NT indicates that progressive diminishment of telomere length may be halted following the initial NT step in order to permit an expanded replicative potential. It is also possible that telomere lengths become expanded during cloning, under the influence of reactivated expression of telomerase, thus restoring an authentic embryonic cellular replicative potential. A third possibility relates to the inherent uncertainties about donor cell origins, and the low efficiency of success of the cloning procedure; specifically, that the rare donor cell nuclei that give rise to the rare surviving clones represent stem cell contaminants in the donor cell population. Stem cells would likely possess longer telomeres than differentiated cells, and yet this greater telomere length would be undetectable by typical Southern blot hybridization of the whole cell population. Stem cells may also possess a greater capacity to activate telomerase expression after SCNT and restore telomere length to counter aging effects evident in differentiated cells (Allsopp et al., 2003). The first of these two possibilities have been examined extensively in a variety of studies of clones of many different species, but the third possibility related to stem cell donor nuclei remains to be examined.

The Wilmut laboratory reported that nuclear transfer can lead to telomere elongation of late-passage donor cells (fibroblasts) used for cloning in sheep, but that the telomeres do not become fully restored relative to early passage cells (Clark et al., 2003). Dolly was reported to have shorter than normal telomeres (Shiels et al., 1999), consistent with incomplete restoration of telomere length (Clark et al., 2003). Observations in cattle indicated that cloned calves could be obtained from senescent fibro-blasts, suggesting an ability to elongate telomeres and thus restore replicative potential (Lanza et al., 2000). Other studies (Tian et al., 2000; Betts et al., 2001) reported cloned calves made using fibroblast nuclei possessed telomeres that were not different from those of control calves, indicating restoration of telomere length relative to donor nuclei. Kato et al. (2000) reported that the observed telomere lengths of clones depended on the cell type assayed; telomere length in ear cells of cloned calves were similar to those of ear cells of the nuclear donor animal, but that telomere length was shorter in white blood cells of clones. Miyashita et al. (2002) reported that donor clones made with muscle and fibroblast cell nuclei had telomeres longer than those of the donor animal, but similar to control calves, whereas clones made with cumulus, mammary epithelial, and oviductal cell nuclei had telomeres shorter than those of control animals. Clones made with embryonic stem cell nuclei appeared to have expanded telomeres. Thus, a donor cell type effect on subsequent telomere length appeared to occur.

The results of Miyashita et al. (2002) may reflect the continued expression of the donor cell program in the early cloned embryo, so that different nuclear donor cell types may direct different levels of expression of telomerase and other factors required for telomere elongation. An alternative explanation for the apparent effect of donor cell type is that the different populations contain different proportions of some form of undif-ferentiated stem cell. If the donor cell gene expression program continues after nuclear transfer, and includes telomerase expression, then such a donor cell nucleus could direct the expression of telomerase and expansion of its own telomeres. The variability seen among different tissues of cloned animals bears further study. Additionally, species-dependent differences in replicative potential, which varies with adult size (Haussmann et al., 2003), could contribute to diversity in observations obtained with different model organisms. Overall, it appears that cloning by SCNT can lead to telomere expansion, but the degree of that expansion is affected by a variety of factors, most notably donor cell type.

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Blood Pressure Health

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