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 not too short and not too long, but just right.
|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.|
The finding, which appears in Nature Structural & Molecular Biology, deepens our understanding of stem cell biology and could help advance stem cell-based therapies, especially related to aging and regenerative medicine.
“This work shows that the optimal length for telomeres 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.”
Karlseder, Rivera, and colleagues began by investigating telomere maintenance in laboratory-cultured lines of human embryonic stem cells (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.
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 pluripotent stem cells (iPSCs), which are differentiated cells (e.g., skin cells) that are reprogrammed back to a stem-cell-like state. They looked at induced pluripotent stem cells (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 induced pluripotent stem cells (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 stem cell therapies and regenerative medicine,” says Rivera.
Citation: Rivera, Teresa, Candy Haggblom, Sandro Cosconati, and Jan Karlseder. “A balance between elongation and trimming regulates telomere stability in stem cells.” Nature Structural & Molecular Biology (2016).
Adapted from press release by Salk Institute.