The researchers conducted their experiments on smooth muscle cells that they genetically engineered. "This gives us a very good model for testing drugs to treat progeria," said Cao, senior author of a research article published in the May 19, 2014 online Early Edition of the
. "And it may help us understand how cardiovascular disease develops in people aging normally."
Progeria is extremely rare—about 100 patients worldwide have been diagnosed—and always fatal at an early age. Patients typically die around age 13. The disorder is difficult to study because patients are so few, and their rapid decline mostly affects internal organs. That makes the effects hard to track without invasive testing, from which researchers want to spare the young patients.
Until now, researchers didn't know what mechanisms might be causing the patients' deaths. They knew a genetic mutation makes patients' cells produce progerin, a toxic form of a protein that, in healthy people, forms the skeletal structure of cell nuclei. In previous studies Cao and others found that progerin builds up in cells of elderly people, suggesting that it is also linked to normal aging. But progerin's effects on smooth muscle cells were unknown before this study.
Studies in mice with a genetically engineered form of progeria found the animals lost most of the smooth muscle cells in their large arteries. This muscle type, involved in involuntary movement, is in the lining of many internal organs, including blood vessels.
Cao's team couldn't obtain human smooth muscle cells from progeria patients for their study because the process would be too invasive, so they used induced pluripotent stem cells—adult cells reprogrammed to behave like embryonic stem cells and develop into a variety of cell types.
In a first for a progeria study, the researchers induced skin cells from progeria patients and normal adults to develop into smooth muscle cells, and then compared cell reproduction and decay in healthy cells with those same processes in cells containing the progeria mutation. Both sets of smooth muscle cells began multiplying, but after two weeks the progeria cells leveled off; as many cells were dying as were reproducing. The researchers discovered that the progeria cells accumulated toxic progerin and had abnormally low levels of PARP-1, a protein that is important in repairing cell damage.
Cells constantly repair damage to their DNA, Cao explained, and they have several ways to get the job done. When one strand in the DNA double helix breaks, cells usually use the unbroken strand as a template to make a perfect copy. PARP-1 is supposed to sense the break and start this repair process. In the study's normal smooth muscle cells, that's what happened.