|Researchers Isolate Adult Stem Cells for First
Time in Tendon
Tendon, the cord-like tissue that connects muscle to bone, contains
a small subset of previously unknown adult stem cells, scientists
at the National Institute of Dental and Craniofacial Research (NIDCR)
part of the National Institutes of Health, and their colleagues
The finding, published online today in the journal Nature
Medicine, points to a natural source of tendon-producing
cells in adults and raises the possibility that, with further
research, these cells one day could help to mend torn or degenerating
tendons that are slow to heal.
Marian Young, Ph.D., an NIDCR scientist and the senior author
on the study, said the findings also bring to light an unexpected
biochemical habitat, or niche, that harbors stem cells. The cells
are embedded between layers of extracellular matrix (ECM), the
chain-like coils of protein that give tendon its elasticity and
contain relatively few cells or blood vessels. To date, most known
adult stem cells occupy cell-rich environments with a ready source
"We read a lot about the promise of stem cells, but sometimes
overlooked is the importance of the niches that surround them," said
Young. "Each individual niche in the body helps to carefully
regulate the activities of a given stem cell. What’s nice is we
have begun to characterize both in tandem, and that gives the field
a head start in learning to meld an understanding of both and hopefully
one day to re-engineer damaged tendon."
According to Young, the stem cells, which her group named tendon
stem/progenitor cells, or TSPCs, would have never been discovered
had it not been for their studies with mice — and good fortune.
Young’s laboratory for several years had been knocking out, or
inactivating, specific genes in developing mice that likely were
involved in forming skeleton and its associated tissues. Among
these genes were those that encoded the structural proteins biglycan
and fibromodulin, major components of the ECM.
Having knocked out the genes for biglycan and fibromodulin in
a new litter of mouse pups, they noticed the mice developed an
unusual gait and had difficulty flexing their limbs at two months
old. Subsequent X-rays provided the reason: Without biglycan and
fibromodulin, the mice were abnormally forming bones within their
Young and her colleagues theorized that the tendons in these mice
might contain stem cells that normally form tendon and, when their
niche is altered, misguidedly create bone. If so, they theorized
the ECM might house the stem cells, and biglycan and fibromodulin
likely played a key role in regulating their normal activity. To
test this theory, Young said she sought the help of her colleague
Songtao Shi, DDS, Ph.D., now a scientist at the University of Southern
California, who had previously discovered stem cells in adult dental
Their speculations turned out to be correct. Yanming Bi, Ph.D.,
a cell biologist in Young’s laboratory, isolated various cells
from mouse and human tendon and cultured them in the laboratory. "Cells
must meet very specific criteria to be termed stem cells," said
Bi, the lead author on the Nature Medicine paper. "They
must produce copies, or clones, of themselves. They must be self
renewing, or proliferate at a rapid rate. Finally, they must display
certain proteins on their cell surface that indicate a capacity
to differentiate into other tissues, such as bone and cartilage."
Bi said the cell culture studies produced a small population of
mouse and human cells that ultimately met all of the criteria.
The obvious next question was whether the TSPCs could actually
form new tendon. In follow-up mouse experiments, they showed both
human and mouse cells formed tissues that resembled tendon and,
characteristic of the tendon, attached to bone.
"These results and the abnormal bones in our earlier mice
strongly suggested that the ECM might serve as the niche for the
stem cells," said Young. "It was a novel idea, and we
wanted to know more about how the ECM might regulate their ability
to produce tendon."
Young said the group first localized the stem cells within the
ECM, confirming their presence in tendon. Thereafter, returning
to experiments with mice that lack the genes for biglycan and fibromodulin,
they showed the loss of these molecules led to the production of
abnormally disorganized structural proteins called collagen, which
form the majority of the ECM. With the change in collagen and thus
the normal stem cell niche, the TSPCs produced bone in these mice
instead of tendon.
"The lesson here is: Follow the phenotype," said Young,
using a term in genetics that means the physical manifestation
that arises when a gene is inactivated. "Without the original
mouse model, we could have never predicted that the stem cells
were present in the extracellular matrix. The phenotype pointed
us in the right direction and got us thinking in the right way."
Young said her group is now attempting to determine whether other
adult stem cells could be prompted in similar niches to form tendon.
If so, they could create a more plentiful supply of tendon-producing
stem cells, which would better enable additional work to characterize
their responses to conditions in the ECM.
"Our understanding of tendon biology is very much a work
in progress," said Young. "The TSPCs give us a needed
early entry point to better understand its developmental and regenerative
"It’s also reasonable to say that the TSPCs one day could
have an important role therapeutically," she continued. "As
millions of Americans know first hand, torn tendons are much slower
to heal than bone injuries, in part because tendons are so blood
vessel poor and that inhibits the regenerative process. Using stem
cells to create new tendon gets around that problem. But to reach
that point, there’s a lot of biology and uncertainty that will
need to be worked out."
The National Institute of Dental and Craniofacial Research (NIDCR)
is the nation's leading funder of research on oral, dental, and
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