Ever since researchers connected the shortening associated with telomeres — the protective structures on the ends associated with chromosomes — to aging and disease, the competition has been on to understand the factors that govern telomere size. Now, scientists at the Salk Institute have found that a stability of elongation and trimming in stem cells leads to telomeres that are, as Goldilocks would say, not way 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 stem cell the field of biology and could help advance stem cell-based therapies, especially associated with aging and regenerative medicine.

“This function shows that the optimal length for telomeres is a carefully controlled range between two extremes, ” says Jan Karlseder, a professor in Salk’s Molecular and Cell The field of biology Laboratory and senior author of the work. “It has been known that very short telomeres cause harm to a cellular. But what was totally unexpected was our finding that harm also occurs when telomeres are very long. ”

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

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

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

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

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

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

“Stem cell reprogramming is a major technological breakthrough, but the methods are still being perfected. Understanding how telomere length is regulated is an important step toward realizing the particular promise of stem cell therapies and regenerative medication, ” says Rivera.

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