Stem Cell Passaging Yields Mice with Longer and Better Telomeres

To elongate telomeres within stem cells, scientists needn’t resort to genetic manipulation. Instead, merely imposing the right culture conditions may suffice, which is good news for those interested in determining whether longer telomeres might confer any medical benefits, such as a lower rate of molecular aging or a decreased incidence of cancer. Yet it hasn’t been clear whether stem cells containing elongated telomeres could give rise to useful animal models, that is, animal models that could demonstrate whether elongated telomeres merit serious consideration, sooner rather than later, in regenerative medicine.

Weighing in on this issue is a team of scientists based at the Spanish National Cancer Research Centre (CNIO). The team, led by María A. Blasco, Ph.D., has succeeded in creating mice in the laboratory with hyper-long telomeres and with reduced molecular aging. The scientists report that they did so while avoiding the use of what to date has been the standard method—genetic manipulation.

Details of the team’s work appeared June 2 in Nature Communications, in an article entitled, “Generation of Mice with Longer and Better Preserved Telomeres in the Absence of Genetic Manipulations.” The article indicates that it is possible to generate mice bearing cells with hyper-long telomeres and that these cells contribute to the normal architecture and function of adult organs. In addition, the mice that harbored hyper-long telomeres showed fewer signs of molecular aging and had a lower incidence of cancer.

“Both hyper-long and normal telomeres shorten with age, but GFP [green fluorescent protein]-positive cells retain longer telomeres as mice age,” wrote the articles’ authors. “Chimeric mice with hyper-long telomeres also accumulate fewer cells with short telomeres and less DNA damage with age, and express lower levels of p53.”

CNIO researchers had previously demonstrated that the in vitro expansion of pluripotent stem cells. For example, in 2009, they described that the in vitro culture of induced pluripotent stem cells (iPSCs) caused the progressive lengthening of telomeres, to the point of generating what the authors called “hyper-long telomeres.” Sometime later, they reported that this phenomenon also occurs spontaneously in embryonic stem cells (ESCs) when cultured in vitro.

“The in vitro expansion of the ESCs results in the elongation of the telomeres up to twice their normal length,” explained the authors of the current study. This lengthening, the authors added, occurs thanks to the active natural mechanisms without alterations in the telomerase gene.

When the scientists participating in the current study generated chimeric mice containing cells with both hyper-long and normal telomeres, the cells with hyper-long telomeres in these mice appeared to be perfectly functional. When the tissues were analyzed at various moments (0, 1, 6, and 12 months of life), these cells maintained the additional length scale (they shortened over time but at a normal rhythm), accumulated less DNA damage, and had a greater capacity to repair any damage. In addition, the animals presented a lower tumor incidence than normal mice.

These results show that pluripotent stem cells carrying hyper-long telomeres can give rise to organisms with telomeres that remain young at the molecular level for longer. According to the authors, this is the “proof of concept means that it is possible to generate adult tissue with longer telomeres in the absence of genetic modifications.”

“Our work,” asserted Dr. Blasco, “demonstrates that it is possible to generate iPSCs with longer telomeres that would turn into differentiated cells also with longer telomeres and that would, therefore, be better protected against damage.” This would be of benefit to the field of regenerative medicine; teams are now studying how to use iPSCs to generate adult cell types for cell therapy.

The next step that the CNIO team is already working on will be to “generate a new species of mice in which the telomeres of all the cells are twice as long as those in normal mice,” explained Dr. Blasco. “Then, we will be able to address some of the important questions that remain unanswered: Would a mouse species with telomeres that are double in length live longer? Is this the mechanism that is used by nature to determine different longevities in genetically similar species? Would this new species present a higher or lower incidence of cancer?