Reverting skin cells from people with a premature aging disease back to a more embryonic state appears to overcome the molecular defect in these cells. People with the disease have abnormally short telomeres, a repetitive stretch of DNA that caps chromosomes and shrinks with every cell division, even in healthy people.
Researchers from Children’s Hospital Boston found that reprogramming the skin cells, using induced pluripotent stem cell technology, lengthened the telomeres in the cells. The reprogramming process activated the telomerase enzyme, which is responsible for maintaining telomeres. The research was published today in the online version of the journal Nature.
The research adds to previous findings suggesting that enhancing activity of the telomerase enzyme might benefit patients with premature aging disorders. The study also provides a new tool for studying telomerase, an enzyme of great interest to scientists working on both aging and cancer. The shortening of telomeres over a lifetime is thought to be tied to aging. And abnormal activation of telomerase in cancer cells allows them to proliferate uncontrollably. While scientists already knew that reprogramming could lengthen telomeres in cells from healthy people, it was unclear if the same could happen in cells with defective telomerase.
Telomerase is most active in stem cells, allowing these cells to maintain their telomere length and divide indefinitely. The telomeres of differentiated cells, such as skin cells, shorten with every cell division, limiting their lifespan. (The discovery of the enzyme in the 1980s was awarded the Nobel Prize in Physiology or Medicine last year.)
People with a premature aging disease called dyskeratosis congenita often have genetic defects in one of the three components of telomerase, producing a range of abnormalities, including in the skin, blood, and gastrointestinal tract. The deadliest defect is an inability to replenish the various types of blood cells, leading to early death from infection or bleeding. “We know that cells from these patients grow very poorly in culture compared to normal cells,” says Inderjeet Dokal, a physician at Barts and The London School of Medicine and Dentistry, in London, who identified the first genes underlying the disease but was not involved in the new research. The disease, which is quite rare, has become of broader interest thanks to a growing focus on the science of telomeres and their role in aging.
In the new study, Suneet Agarwal, a physician and researcher at Children’s Hospital, and collaborators took skin cells from three patients with the disease and genetically engineered the cells to express a set of genes that triggers reprogramming, reverting the cells to an embryonic state. They were surprised to find that the reprogrammed cells grew and divided, their telomeres lengthening with subsequent divisions.
“They show that they can make the cells young,” says Lorenz Studer, a physician and scientist at Memorial Sloan-Kettering Cancer Center, in New York, who was not involved in the research. The defect in the telomerase enzyme “seems to be repressed or overridden during reprogramming, which probably explains why patients do reasonably well in the early stages of life,” he says. “Patients still have same mutation whether in the [skin cell] or iPS cell, but the mutation only manifests itself in the differentiated cell.”
The researchers found that reprogramming appeared to activate a specific component of the telomerase enzyme, a discovery that they hope to use to develop new treatments for this and other telomerase-related diseases. Agarwal hopes to search for drugs that boost the enzyme.
“This disease is an ideal case for the clinical application of telomere-rejuvenated adult stem cells or iPS cell therapies, because the primary defect of telomerase deficiency does not need to be corrected if telomerase function can be temporarily stimulated enough to elongate telomeres,” wrote Kathleen Collins, a biologist at the University of California, Berkeley, in an e-mail. “This work shows that the iPS state does exactly that.”
The findings are an early example of the potential of induced pluripotent cell reprogramming, a technology first developed in 2007 as a tool for studying human disease. The technique, in which genetic engineering or chemicals are used to activate genes normally expressed in embryonic cells, allows scientists to create stem cells from patients with different diseases. The hope is that differentiating these cells into the cell type affected by the disease will allow researchers to study the molecular mechanisms that cause it.
Studer points out that the new research could shed light on how the age or telomere status of a cell might affect how it manifests a particular disease. For example, it’s not yet clear whether cells derived from patients with an age-related disease, such as Parkinson’s or Alzheimer’s, will show signs of the disease soon after reprogramming, or if the cells must age–cycling through a number of cell divisions–to more accurately reflect age-related ailments.
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