May 05, 2004
Insulin-Producing Pancreatic Cells Are Replenished by Duplication
Howard Hughes Medical Institute (HHMI) researchers at Harvard
University have discovered that insulin-producing beta cells in the
pancreas that are attacked in type 1 diabetes are replenished through
duplication of existing cells rather than through differentiation of
adult stem cells.
Although the experiments, which were done using mice, do not rule
out the possibility that there are adult stem cells in the pancreas,
the researchers say that they do suggest strongly that embryonic stem
cells or mature beta cells may be the only way to generate beta cells
for use in cell replacement therapies to treat diabetes.
The research team, which was led by HHMI investigator Douglas
A. Melton at Harvard University, reported its findings in a
research article published in the May 6, 2004, issue of the journal
Nature. Melton's co-authors include Yuval Dor, Juliana Brown and
Olga I. Martinez, all of Harvard.
In cell culture, embryonic stem (ES) cells retain the properties of
undifferentiated embryonic cells. ES cells have the capacity to make
all cell types found in an adult organism. One of the most hotly
debated questions in biology is whether adult stem cells, which have
been isolated from blood, skin, brain and other organs, have the same
developmental capacity as ES cells.
Researchers have known for some time that ES cells can give rise to
pancreatic beta cells during development. “But the more
interesting question for us has been what happens in mature pancreatic
tissue to both maintain the pancreas and to regenerate it,” said
Melton. “Previous studies have suggested that there are sources
of adult stem cells that might give rise to beta cells. However, those
studies had largely depended on histological `snapshots' of
tissues.” Those snapshots can only suggest the
“geographic” origin of new beta cells and not the identity
of the cells from which they arise, Melton noted.
Melton and his colleagues knew that they could finally put such
questions to rest if they could tag beta cells in such a way that that
they could determine unequivocally whether the new cells were made from
existing beta cells or from a different reservoir of stem cells. For
these studies, they devised a “genetic lineage tracing”
technique that involved engineering a mouse whose beta cells contained
a telltale genetic marker that could be switched on by administering
the drug tamoxifen to the mice.
The logic behind the technique is relatively straightforward: When
the researchers administer tamoxifen to the adult mice, they can easily
follow the marker to determine whether it is inherited by subsequent
generations of beta cells. If it is inherited, then the cells
expressing the marker are the offspring of pre-existing beta cells.
When the researchers applied their technique to the mice, they
discovered that all the new beta cells they examined — whether arising
in the usual process of renewal or during regeneration following
partial removal of the pancreas - were generated from pre-existing beta
cells. According to Melton, the finding highlights a largely
unappreciated capability of beta cells.
“No one has really paid much attention to the replicative
capacity of the beta cell,” he said. “And this work shows
the cells to have a significant proliferative capacity that could be
clinically useful.”
According to Melton, the findings might have implications for
developing treatments for type 1 diabetes, a disease that destroys beta
cells. “If such people have residual beta cells, these findings
suggest that a useful clinical direction would be to find a way to
boost the proliferative capacity of those beta cells, to restore
insulin production in such patients.
“On the other hand, if type 1 diabetics don't have any beta
cells left, then these findings suggest that the only source of new
beta cells is probably going to be embryonic stem cells, because there
don't appear to be adult stem cells involved in
regeneration.”
Melton emphasized that although the results by his group cannot rule
out the existence of beta-cell-producing adult stem cells, “they
raise the bar on trying to demonstrate their existence. In these
experiments, we find no evidence for the existence of adult pancreatic
stem cells,” he said.
The genetic lineage tracing technique devised by Melton's group is a
tool that can now be used to trace the origin of cells involved in the
maintenance and repair of other types of tissue. Melton and his
colleagues are already using the technique to determine the origin of
new cells in lung tissue. And it should be possible to apply the
technique to understand the origin of cancer cells in tumors or to
understand the role of stem cells in such malignancies, Melton
said.
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