Researchers turn one form of adult mouse cell directly into another
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(PhysOrg.com) -- In a feat of biological prestidigitation likely to
turn the field of regenerative medicine on its head, Harvard Stem Cell
Institute (HSCI) co-director Doug Melton and post doctoral fellow Qiao
"Joe" Zhou re****t having achieved what has long been a dream and
ultimate goal of developmental biologists =80 =92=B6 directly turning one
type
of fully formed adult cell into another type of adult cell.
The Melton team re****ts in today's online edition of the journal
Nature that, using a technique it is calling "direct reprogramming, "
the team is able to turn mouse exocrine cells, which make up about 95
percent of the pancreas, into precious and rare insulin-producing beta
cells. These beta cells, which comrpise about one percent of the
pancreas, are the cells that die off in Type I diabetes.
In addition to its value for the field of regenerative medicine, the
work also is a major step forward toward eventually developing a
treatment for Type II =80 =92=B6 and eventually Type I =80 =92=B6
diabete=
s, a
treatment
that might someday eliminate the need for patients to constantly
monitor their blood sugar and take insulin-adjusting medications, or
even insulin. It is im****tant to note, however, that there are
numerous scientific hurdles that lay ahead before a treatment could be
tested in humans.
Melton, a Howard Hughes Medical Institute Investigator, has discussed
the work in general terms at a few scientific meeting over the course
of the last few months, and his talks have generated expressions of
surprise from those who have heard them, or even heard about them.
George Q. Daley, immediate past president of the International Society
for Stem Cell Research and a member of HSCI's Executive Committee,
said Melton's findings are of a caliber that "will revolutionize what
is already a revolutionary field."
Unlike the process involved in creating induced pluripotent stem cells
(iPS), which have caused enormous excitement ever since their
introduction two years ago by Japanese researcher ****nya Yama****a,
this direct reprogramming technique does not require turning adult
cells into stem cells and then figuring out how to induce them to
differentiate into a desired cell type. Melton emphasized, however,
that direct reprogramming does not in any way eliminate the need for,
or value of, work with iPS cells or human embryonic stem cells. "We
need to attack problems from multiple angles," said Melton, stressing
that his lab is using several approaches and will continue to work
with iPS and hES cells.
Sir John Gurden, the internationally renowned developmental biologist
under whom Melton did his graduate work at Oxford University and the
first scientist to successfully clone an adult mammal - a frog, said
that "What you really want is a missing cell type, one that is not
functioning properly to be derived from something else. But you only
want that cell type. So I think this is a really im****tant step
forward in exercising what people really wanted and showing how well
it can work, by this gene over-expression procedure."
As is the case with all iPS work thus far, Melton's experiments
involved using viruses to integrate the transcription factors into the
target cells. Because of the risks that approach would pose to humans,
the team is looking for chemicals that might effectively and, most
im****tant, safely replace the viruses.
Joan Brugge, Chair of the Department of Cell Biology at Harvard
Medical School, said the new study "provides exciting new insights
into yet another aspect of cell plasticity that was not appreciated
previously and that offers great potential therapeutically. Direct
reprogramming represents a more straight-forward strategy to treat
diseases involving loss of function of specific cell populations than
approaches requiring an intermediate embryonic stem cell," she said.
Whitehead Institute stem cell researcher Rudolf Jaenisch, who has
heard one of Melton's presentations on the new work, said that there
had previously been so much empty talk about supposedly successful
direct reprogramming efforts that if anyone other than Doug Melton
were publi****ng this re****t Jaenisch would view it quite skeptically.
In fact, even Melton was "more than a little surprised to find that we
could use a combination of just three transcription factors to
reprogram one cell type into another." He said that first author Joe
Zhou's experiments "combined a systematic approach to identifying the
relevant transcription factors, hard work, and a bit of luck."
Luck, serendipity, is virtually always a part of the process of
scientific discovery. But the choice of transcription factors Ngn3,
Pdx1, and MafA, while lucky, could hardly be said to have resulted
from luck. Instead, it was the product of two years of repetitive lab
work that began, Melton said, "by asking what genes you have to have
turned on in the cell for it to become a beta cell.
"If you want to do reprogramming it doesn't take great insight to
figure out that the key genes are transcription factors =80 =92=B6 the
proteins
that bind DNA and tell cells which genes to turn on and which to turn
off," said Melton, the co-chairman of Harvard's new Department of Stem
Cell and Regenerative Biology.
Melton likened the the multi-step process a stem cell goes through
during differentiation into a specific adult cell type to passing
through a series of doors. "There are locks on all the doors," he
said, "and the locks are transcription factors. We asked which ones
are present in the beta cell, and that gave us 1,100 transcription
factors to choose from. Eventually we learned that of the 1,100, only
about 200 are actually expressed in cells that are involved in forming
the pancreas.
"Next," Melton continued, "we decided that of the 200, we only cared
about the ones that are expressed in the key part of the pancreas
where the beta cells are =80 =92=B6 and that got us down to about 28.
Then
we
did some lineage studies," he explained, "and we got it down to nine.
Joe said, 'my best guess is it's these nine.' And he were right. It
was a messy experiment, mixing all nine and injecting them into the
pancreas. Then we found out that it got better and better as we
removed one gene at a time from the nine, and eventually we found that
it actually works best with three transcription factors =80 =92=B6 that
si=
x
of
them aren't that im****tant. And that's the fun of science!" Melton
said, a grin spreading across his face.
But back to serendipity for a moment:
Suppose the experiment hadn't worked with those nine transcription
factors; what then? "If it hadn't worked with those nine, we'd
probably have dropped the experiment and gone onto something else;
there would have been just too many possible combinations of
transcription factors to wade through," Melton said.
"We're intrigued by the possibility that this approach, which has
worked for pancreatic insulin-producing cells, could be more widely
applied to many kind of cells, especially those that are lost in
disease or following injury," Melton said. "And at the same time, we
are exploring the possibility of using this general approach in a
clinical context to make new beta cells for patients."
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