Telomere shortening and decline in replicative potential as a function of donor age in human adrenocortical cells

Yang, Luodan; Suwa, Tetsuya; Wright, Woodring E.; Hornsby, Peter J.

doi:10.1016/s0047-6374(01)00280-9

Cited by 64 publications

(44 citation statements)

References 22 publications

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“…Examining fibroblasts, Hayflick was the first to propose that these parameters were inversely correlated (Hayflick, 1965). Since then several studies have shown such a relationship in many cell types, including keratinocytes (Rheinwald and Green, 1975), endothelial cells (Hoshi and McKeehan, 1986) and adrenocortical cells (Yang et al, 2001). …”

Section: Discussionmentioning

confidence: 99%

Correlation between the donor age and the proliferative lifespan of human peritoneal mesothelial cells in vitro: Is TGF-β1 a link?

Książek¹,

Winckiewicz²,

Staniszewski³

et al. 2007

Experimental Gerontology

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Section: Discussionmentioning

confidence: 99%

Correlation between the donor age and the proliferative lifespan of human peritoneal mesothelial cells in vitro: Is TGF-β1 a link?

Książek¹,

Winckiewicz²,

Staniszewski³

et al. 2007

Experimental Gerontology

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“…Bovine cells divide at a much higher rate than human adrenocortical cells. Human adrenocortical cell proliferation is dependent on donor age (Yang et al 2001), but even fetal human adrenocortical cells do not match the rate of proliferation of primary bovine adrenocortical cells. Nevertheless, telomerase activity was weakly detected in primary human adrenocortical cells.…”

Section: Discussionmentioning

confidence: 99%

“…Clones of normal bovine adrenocortical cells undergo loss of telomeric DNA in culture and eventually enter replicative senescence (Thomas et al 2000). Similarly, human adrenocortical cells have a finite proliferative potential in culture (Hornsby et al 1992) and this is also associated with telomere shortening (Yang et al 2001). When bovine adrenocortical cells were transfected with a combination of plasmids encoding human TERT (hTERT) (under the control of the CMV promoter) and SV40 T antigen (under the control of the SV40 promoter), telomere length was stabilized, cells showed a high level of telomerase activity, and were apparently immortalized (Thomas et al 2000).…”

Section: Introductionmentioning

confidence: 99%

“…hTERT-modified clones could be transplanted into adrenalectomized scid mice and rescued the animals from the lethal effects of adrenalectomy by the formation of functional adrenocortical tissue (Thomas et al 2000). Both human and bovine adrenocortical cells show telomere length stabilization and apparent immortalization following infection with a retrovirus encoding hTERT (Yang et al 2001). In summary, previous experiments have shown that normal bovine adrenocortical cell clones and genetically modified clones not transfected with hTERT suffer telomere shortening, are telomerase-negative, and have a finite proliferative potential, whereas both bovine and human adrenocortical cells expressing hTERT have stabilized telomere lengths and are apparently immortalized.…”

Section: Introductionmentioning

confidence: 99%

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Telomerase activity in primary cultures of normal adrenocortical cells

Suwa¹,

Yang²,

Hornsby³

2001

Journal of Endocrinology

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Telomerase activity was measured in isolated cells from bovine and human adrenal cortex, in cells in primary culture, in cells in later passages in culture, and in cells genetically modified by expression of hTERT (human telomerase reverse transcriptase). Telomerase activity in freshly isolated bovine adrenocortical cells and in human adrenal cells from donors of various ages (6-79 years) was very low or undetected. However, primary bovine adrenocortical cell cultures were strongly positive for telomerase activity, and primary human adrenocortical cell cultures were weakly positive. Both cell types proliferate in primary culture but proliferation of bovine cells is much more vigorous. When primary bovine cells were subcultured to make successively secondary and tertiary cultures, telomerase activity declined strongly, and was undetected by the third passage. There was only a slight decrease in growth rate over this period. Levels of the telomerase RNA component did not change with passage number when assessed by semi-quantitative competitive RT-PCR. When both bovine and human cells were infected with a retrovirus encoding hTERT, telomerase activity in the cells was very high. We conclude that in the adrenal cortex, as in some other tissues, TERT expression is regulated and upregulation of telomerase activity is associated with rapid proliferation in primary culture. Telomerase activity is not maintained, and introduction of TERT is required for stable telomerase activity and for immortalization.

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“…We have generated hTERT-modified bovine and human adrenocortical cells (Thomas et al, 2000;Suwa et al, 2001;Yang et al, 2001;Hornsby, 2004). For both bovine and human adrenocortical cells, we find that when culture conditions are optimized, ectopic expression of hTERT appears to be the only requirement for immortalization (Thomas et al, 2000;Yang et al, 2001;Hornsby, 2004).…”

Section: Safety Of Htert-immortalized Cells: Transplantation Of Normamentioning

confidence: 99%

Improving cell therapy—experiments using transplanted telomerase-immortalized cells in immunodeficient mice

Huang

Chen

Liang

et al. 2007

Mechanisms of Ageing and Development

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Cell therapy is the use of stem cells and other types of cells in various therapies for age-related diseases. Two issues that must be addressed before cell therapy could be used routinely in medicine are improved efficacy of the transplanted cells and demonstrated long-term safety. Desirable genetic modifications that could be made to cells to be used for cell therapy include immortalization with hTERT (human telomerase reverse transcriptase). We have used a model for cell therapy in which transplantation of adrenocortical cells restores glucocorticoid and mineralocorticoid hormone levels in adrenalectomized immunodeficient mice. In this model, clones of cells that had been immortalized with hTERT were shown to be able to replace the function of the animals'adrenal glands by forming vascularized tissue structures when cells were transplanted beneath the capsule of the kidney. hTERT-modified cells showed no tendency for neoplastic changes. Moreover, a series of experiments showed that hTERT does not cooperate with known oncoproteins in tumorigenesis either in adrenocortical cells or in human fibroblasts. Nevertheless, hTERT was required for tumorigenesis when cells were implanted subcutaneously rather than in the subrenal capsule space. Changes in gene expression make hTERT-modified cells more robust. Understanding these changes is important so as to be able to separately control immortalization and other desirable properties of cells that could be used in cell therapy. Alternatively, desirable properties of transplants might be provided by cotransplanted mesenchymal cells: mesenchymal cell-assisted cell therapy. For both hTERT modification and mesenchymal cell-assisted cell therapy, genomics approaches will be needed to define what genetic modifications are desirable and safe in cells used in cell therapy.

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Telomere shortening and decline in replicative potential as a function of donor age in human adrenocortical cells

Cited by 64 publications

References 22 publications

Correlation between the donor age and the proliferative lifespan of human peritoneal mesothelial cells in vitro: Is TGF-β1 a link?

Correlation between the donor age and the proliferative lifespan of human peritoneal mesothelial cells in vitro: Is TGF-β1 a link?

Telomerase activity in primary cultures of normal adrenocortical cells

Improving cell therapy—experiments using transplanted telomerase-immortalized cells in immunodeficient mice

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