Growing Human Skin In Laboratory Can Prematurely Age Cells
Technique used to save lives also means skin prematurely ages
Tuesday, April 22, 2003
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."