Making a Mouse that Exhibits Human Telomere Dynamics
Telomerase acts to extend telomeres, the repeated DNA sequences at the ends of chromosomes. With every cell division, some of the telomere repeats are lost. Cells with critically short telomeres become senescent or undergo programmed cell death, having reached the Hayflick limit on replication. Some cells employ telomerase to adjust the countdown of telomere length. In humans, only stem cells use telomerase. In other species, such as mice, telomerase is much more widely expressed. There has been some interest in the research community in upregulation of telomerase as a way to improve stem cell and tissue function in old age.
One of the points of risk in bringing telomerase gene therapies to the clinic is that while the results to date in mice have been impressive, gene therapies producing extended life, improved function, reduced cancer incidence, mice have very different telomere dynamics from humans. Will the risk of extending the functional life of damaged, potentially cancerous somatic cells be offset by improved immune function in humans as it seems to be in mice? While some number of people have undergone telomerase gene therapy, largely via medical tourism, results for most of those patients will never be published, and long-term data on cancer risk will in any case take years to emerge.
In today's open access paper, researchers report on the development of a mouse lineage with a humanized telomerase gene and more human-like telomere dynamics. This will be a useful tool in the continued development of telomerase gene therapies. If telomerase gene therapy in this lineage turns out to produce much the same benefits as it does in wild type mice, with particular attention to cancer incidence, then one could be more convinced that risks in human patients are lower.
Humanization of the mouse telomerase gene reset telomeres to human length
Telomeres undergo shortening with each cell division, serving as biomarkers of human aging, which is characterized by short telomeres and restricted telomerase expression in adult tissues. Contrarily, mice, featuring their longer telomeres and widespread telomerase activity, present limitations as models for understanding telomere-related human biology and diseases. To bridge this gap, we engineered a mouse strain with a humanized mTert gene, hmTert, wherein specific non-coding sequences were replaced with their human counterparts. The hmTert gene, encoding the wildtype mTert protein, was repressed in adult tissues beyond the gonads and thymus, closely resembling the regulatory pattern of the human TERT gene.
Remarkably, the hmTert gene rescued telomere dysfunction in late generations of mTert-knockout mice. Through successive intercrosses of Tert(h/-) mice, telomere length progressively declined, stabilizing below 10-kb. Tert(h/h) mice achieved a human-like average telomere length of 10-12 kb, contrasting with the 50-kb length in wildtype C57BL/6J mice. Despite shortened telomeres, Tert(h/h) mice maintained normal body weight and cell homeostasis in highly proliferative tissues. Notably, colonocyte proliferation decreased significantly in Terth/h mice during dextran sodium sulfate-induced ulcerative colitis-like pathology, suggesting limitations on cellular renewal due to short telomeres.
Our findings underscore the genetic determination of telomere homeostasis in mice by the Tert gene. These mice, exhibiting humanized telomere homeostasis, serve as a valuable model for exploring fundamental questions related to human aging and cancer.