Growing Human Skin In Laboratory Can Prematurely Age Cells
Children who receive laboratory-expanded sheets of their own skin to cover severe burns are saved from certain death, but their new skin can have the cellular age of an 80 year old, according to a study at Duke University Medical Center.
The process of growing small patches of human skin into larger sheets, called tissue engineering, makes cells divide so many times that the skin becomes prematurely aged at a cellular level. The dangers of prematurely aged skin are that it will not regenerate for the duration of the child's life, and its wound-healing capacity could be severely compromised, said Christopher Counter, Ph.D., a cancer biologist in the Duke Comprehensive Cancer Center.
Results of his study are published in the April 19, 2003, issue of the British medical journal, The Lancet.
"Although tissue engineering is a life-saving technique, our work suggests that the skin could ultimately lose its regenerative capacity over a period of decades," said Counter. "Conversely, we might unwittingly select cells that have a mutation and keep dividing uncontrollably in the patient, which is a hallmark of cancer." To date, tissue engineering has saved more than 700 patients who had burns covering more than 75 percent of their bodies, and, he points out, so far most of these grafts are fine.
To determine the cellular age of expanded skin grafts, Counter's team analyzed samples from four burn victims years after they received "cultured" skin grown in the laboratory. Culturing the skin involves taking small patches of undamaged skin from the patient and placing them in a large dish, where the skin cells divide and multiply to form a sheet.
The cultured sheets of skin are then placed over the patient's burned tissue. Within days, the skin sheets permanently engraft, attaching to the healing connective tissue in the wound bed. Because the skin is autologous, or derived from the patient, there is no chance of rejection. Such a process is used when there is not enough of the patients' unburned skin to cover expansive, third degree burns.
Counter said that years after the engraftment, the skin continues to look normal. But a closer analysis of cultured skin showed extensive changes in the chromosomes of skin cells.
Specifically, Counter and co-investigators William Press and Carolyn Compton found that cultured skin cells had much shorter chromosomal tips than did normal skin cells. Chromosomes are the strands of DNA in each cell that carry its genetic code, and the end of a chromosome is its "telomere." Every time a cell divides, its chromosomal telomeres become shorter until they are so short that the cell receives a signal to commit suicide.
The exponential cell division that skin patches undergo during the expansion process caused telomeres to become excessively short, analogous to the skin of an 80 year old, said Counter. This aging process is what he speculates might curtail the lifespan of the skin.
Counter said evidence of this phenomenon is strong, both from human and animal studies. Certain skin diseases such as dyskeratosis congenita cause telomeres to become excessively short, resulting in skin defects and reduced wound-healing capacity, he added.
"In fact in every organism ever tested, ranging from yeast to mice to humans, extensive loss of telomeric DNA has the same consequence: a reduction in the proliferative capacity of the cells," Counter said.
Counter and his team speculate that briefly adding an enzyme, called telomerase, during the laboratory expansion process might elongate telomeres enough that they would sustain their regenerative capacity. Telomerase is produced by highly proliferative cells, such as adult stem cells, in order to prolong their lifespan. Yet telomerase produced by the wrong cells in the body can unnaturally extend the cell's life and hence promote the growth of cancer. In fact, recent studies have shown that telomerase is found in 85 percent of all cancers.
Using telomerase briefly and at the right timeframe during skin growth might allow telomeres to be appropriately long without stimulating the over-growth that is characteristic in all cancer, said Counter. "Not only does our data have relevance to the burn victims, but also is a red flag that other tissues engineered in the lab may run into the same problem."