Scientists find that for stem cells to be healthy, telomere length has to be just right

December 5, 2016, Salk Institute
Immunofluorescence analysis of pluripotent markers Nanog (red) and TRA-1-60 (green) in human induced pluripotent stem cells derived from skin fibroblasts. DNA is shown in blue. Credit: Salk Institute

Ever since researchers connected the shortening of telomeres—the protective structures on the ends of chromosomes—to aging and disease, the race has been on to understand the factors that govern telomere length. Now, scientists at the Salk Institute have found that a balance of elongation and trimming in stem cells results in telomeres that are, as Goldilocks would say, not too short and not too long, but just right.

The finding, which appears in the December 5, 2016, issue of Nature Structural & Molecular Biology, deepens our understanding of and could help advance stem cell-based therapies, especially related to aging and regenerative medicine.

"This work shows that the optimal length for is a carefully regulated range between two extremes," says Jan Karlseder, a professor in Salk's Molecular and Cell Biology Laboratory and senior author of the work. "It was known that very short telomeres cause harm to a cell. But what was totally unexpected was our finding that damage also occurs when telomeres are very long."

Telomeres are repetitive stretches of DNA at the ends of each chromosome whose length can be increased by an enzyme called telomerase. Our cellular machinery results in a little bit of the telomere becoming lopped off each time cells replicate their DNA and divide. As telomeres shorten over time, the chromosomes themselves become vulnerable to damage. Eventually the cells die. The exception is , which use telomerase to rebuild their telomeres, allowing them to retain their ability to divide, and to develop ("differentiate") into virtually any cell type for the specific tissue or organ, be it skin, heart, liver or muscle—a quality known as pluripotency. These qualities make stem cells promising tools for regenerative therapies to combat age-related cellular damage and disease.

"In our experiments, limiting compromised pluripotency, and even resulted in stem cell death," says Teresa Rivera, a Salk research associate and first author of the paper. "So then we wanted to know if increasing telomere length increased pluripotent capacity. Surprisingly, we found that over-elongated telomeres are more fragile and accumulate DNA damage."

Karlseder, Rivera and colleagues began by investigating telomere maintenance in laboratory-cultured lines of human (ESCs). Using molecular techniques, they varied telomerase activity. Perhaps not surprisingly, cells with too little telomerase had very short telomeres and eventually the cells died. Conversely, cells with augmented levels of telomerase had very long telomeres. But instead of these cells thriving, their telomeres developed instabilities.

""We were surprised to find that forcing cells to generate really long telomeres caused telomeric fragility, which can lead to initiation of cancer," says Karlseder, who also holds the Donald and Darlene Shiley Chair. "These experiments question the generally accepted notion that artificially increasing telomeres could lengthen life or improve the health of an organism."

The team observed that very long telomeres activated trimming mechanisms controlled by a pair of proteins called XRCC3 and Nbs1. The lab's experiments show that reduced expression of these proteins in ESCs prevented telomere trimming, confirming that XRCC3 and Nbs1 are indeed responsible for that task.

Next, the team looked at induced (iPSCs), which are differentiated cells (e.g., skin cells) that are reprogrammed back to a stem cell-like state. iPSCs—because they can be genetically matched to donors and are easily obtainable—are common and crucial tools for potential stem cell therapies. The researchers discovered that iPSCs contain markers of telomere trimming, making their presence a useful gauge of how successfully a cell has been reprogrammed.

"Stem cell reprogramming is a major scientific breakthrough, but the methods are still being perfected. Understanding how telomere length is regulated is an important step toward realizing the promise of and regenerative medicine," says Rivera.

Explore further: $89 test kit claims to determine how well your cells are aging. Does it work?

More information: A balance between elongation and trimming regulates telomere stability in stem cells, nature.com/articles/doi:10.1038/nsmb.3335

Related Stories

$89 test kit claims to determine how well your cells are aging. Does it work?

November 28, 2016
A new $89 test claims to calculate the age of the DNA in your cells and tell you how well you are aging. The test, called TeloYears, is the newest in a bunch of mail-order kits that measure the length of telomeres, the caps ...

Researchers uncover key mechanisms of cancer, aging and inflammation

November 7, 2016
A team of University of Pittsburgh researchers has uncovered new details about the biology of telomeres, "caps" of DNA that protect the tips of chromosomes and play key roles in a number of health conditions, including cancer, ...

Scientists create mice with hyper-long telomeres without altering the genes

June 2, 2016
The Telomeres and Telomerase Group at the Spanish National Cancer Research Centre (CNIO), in collaboration with the Centre's Transgenic Mice Core Unit, has succeeded in creating mice in the laboratory with hyper-long telomeres ...

Mouse study links heart regeneration to telomere length

May 30, 2016
Researchers at the Spanish National Center for Cardiovascular Research have discovered that the ends of heart muscle cell chromosomes rapidly erode after birth, limiting the cells' ability to proliferate and replace damaged ...

New method detects telomere length for research into cancer, aging

June 29, 2016
UT Southwestern Medical Center cell biologists have identified a new method for determining the length of telomeres, the endcaps of chromosomes, which can influence cancer progression and aging.

Recommended for you

Bioengineered soft microfibers improve T-cell production

January 18, 2018
T cells play a key role in the body's immune response against pathogens. As a new class of therapeutic approaches, T cells are being harnessed to fight cancer, promising more precise, longer-lasting mitigation than traditional, ...

Weight flux alters molecular profile, study finds

January 17, 2018
The human body undergoes dramatic changes during even short periods of weight gain and loss, according to a study led by researchers at the Stanford University School of Medicine.

Secrets of longevity protein revealed in new study

January 17, 2018
Named after the Greek goddess who spun the thread of life, Klotho proteins play an important role in the regulation of longevity and metabolism. In a recent Yale-led study, researchers revealed the three-dimensional structure ...

The HLF gene protects blood stem cells by maintaining them in a resting state

January 17, 2018
The HLF gene is necessary for maintaining blood stem cells in a resting state, which is crucial for ensuring normal blood production. This has been shown by a new research study from Lund University in Sweden published in ...

Magnetically applied MicroRNAs could one day help relieve constipation

January 17, 2018
Constipation is an underestimated and debilitating medical issue related to the opioid epidemic. As a growing concern, researchers look to new tools to help patients with this side effect of opioid use and aging.

Researchers devise decoy molecule to block pain where it starts

January 16, 2018
For anyone who has accidentally injured themselves, Dr. Zachary Campbell not only sympathizes, he's developing new ways to blunt pain.

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.