Stanford Fruit-Fly Study Adds Weight to Theories About Another Type of Adult Stem...

Stanford Fruit-Fly Study Adds Weight to Theories About Another Type of Adult Stem Cell

STANFORD, Calif.--(Business Wire)--
It turns out that an old dog -- or at least an old fruit-fly cell
-- can learn new tricks. Researchers at the Stanford University School
of Medicine have found that mature, specialized cells naturally
regress to serve as a kind of de facto stem cell during the fruit-fly
life cycle.

The surprising discovery counters the common belief that the
ability to form new cell types or tissues wanes as a cell becomes more
specialized.

"It was mind-boggling, because it went completely against what we
had expected to see happening," said lead researcher Molly Weaver,
PhD. "Once we figured out what was happening, however, the results
were very clear." Weaver is a postdoctoral scholar in the laboratory
of Mark Krasnow, MD, PhD, professor and chair of biochemistry.

Harnessing this type of developmental backtracking in adult human
cells would allow researchers to explore new avenues for treating many
human diseases. Although recent research has shown that human skin
cells can be coaxed in a laboratory dish to generate many other types
of cells, the conversion requires the use of viruses to deliver
specific combinations of genes into the cells. The existence in humans
of similar, naturally occurring stem cell understudies, called
"facultative stem cells," has recently been proposed, but the idea
remains controversial.

"In the past, many believed that cell specialization, or
differentiation, was a terminal state -- there was no going back or
getting young again," said Krasnow, the senior author of the research.
"But now, not only do we know this reversion happens naturally, we
also have a very tractable genetic system in which to study it."

The research will be published online Aug. 1 in Science Express.

Weaver, who is also Howard Hughes Medical Institute fellow of the
Life Sciences Research Foundation, didn't start out trying to
overthrow stem cell paradigms. Fruit flies, or Drosophila, have a long
and illustrious history as laboratory guinea pigs. Weaver was simply
investigating how the respiratory system of the fly is remodeled when
the animal transforms from a tiny, grublike larva into a full-fledged,
winged fly lusting after your bananas and apples.

Like all insects, fruit flies don't have lungs and their blood
doesn't carry oxygen to their tissues. Instead they "breathe" through
tiny openings along their bodies called spiracles. These spiracles
connect to a complex system of tubes called trachea that penetrate the
tissue to deliver oxygen and carry away carbon dioxide. In fruit
flies, the trachea branch from a structure running the length of the
animal called the dorsal trunk.

During metamorphosis, nearly all the larval cells are replaced by
cells arising from structures called imaginal discs. The
undifferentiated cells of these discs bide their time during the
larval stage and only spring into action when the time comes to begin
dividing to produce the tissues of the adult fly.

Weaver and Krasnow, who is also a Howard Hughes Medical Institute
investigator, wanted to know what happened to the tracheal system
during the fly's switch from squirmer to hoverer. They looked at fruit
flies that had been genetically modified so that proliferating cells
in the trachea expressed a highly visible green fluorescent protein,
allowing the researchers to track the fate and location of the cells
by looking for those that glowed green under a microscope.

Then things got interesting. Although the trachea branch from
either side of the dorsal trunk, only one side has imaginal cells. The
expectation has always been that these cells migrate across the dorsal
trunk to repopulate both sides of the trachea with a
flying-appropriate blend of cell types. But, despite spending
countless hours behind a microscope, Weaver never saw any green cells
making their way to the other side.

"I had about four different hypotheses to explain why I couldn't
see any of these cells crossing the dorsal trunk," said Weaver. "It
took quite a while to convince ourselves what was truly going on."

Further experiments that followed the fate of individual stalk
cells in live fruit flies proved that a group of well-differentiated
cells known as the anterior dorsal branch stalk cells were actually
stepping in to repopulate the side of the trachea lacking imaginal
cells. As a result, the researchers concluded that a single tissue was
being remodeled by two types of multipotent cells: one, the
undifferentiated imaginal cells held in reserve to repopulate the
fruit fly body, and the other, a highly specialized cell that reverses
its developmental course in order to give rise to different cell
types.

"To find two very different kinds of progenitor cells in a single
fruit-fly tissue raises the possibility that there may be more than
one kind of adult stem cell in mammalian tissue," said Krasnow. "It
may be that organisms use both quiescent, undifferentiated cells and
more highly differentiated yet reversible facultative stem cells under
different conditions."

Weaver and Krasnow plan to compare molecular and genetic
characteristics of the anterior dorsal branch stalk cells and the
imaginal cells in the trachea in an effort to identify how the stalk
cells are able to re-attain such developmental flexibility. They have
already noticed that, contrary to surrounding cells that accumulate
more than two sets of chromosomes through a process called
endoreplication, the stalk cells have smaller nuclei and don't form
extra sets of chromosomes -- differences that may allow the stalk
cells to more easily re-enter the cell cycle.

"Although it wasn't expected, Drosophila have clearly taken
advantage of this biological capacity during metamorphosis," said
Krasnow. "The stem cell community is debating whether every mammalian
tissue relies on conventional adult stem cells of the sort already
identified in bone marrow and muscle, or if instead there are
facultative stem cells that can arise from differentiated cells within
the tissue. Now we know that it doesn't necessarily have to be one or
the other. It could be both."

The research was supported by the Howard Hughes Medical Institute
and Life Sciences Research Foundation.

Stanford University Medical Center integrates research, medical
education and patient care at its three institutions -- Stanford
University School of Medicine, Stanford Hospital & Clinics and Lucile
Packard Children's Hospital at Stanford. For more information, please
visit the Web site of the medical center's Office of Communication &
Public Affairs at http://mednews.stanford.edu.

(NOTE TO REPORTERS: An image showing the growth of the cells can
be downloaded at
http://med.stanford.edu/news_releases/2008/download/fruit-fly.html)

Stanford University Medical Center
Krista Conger, 650-725-5371 (Print Media)
kristac@stanford.edu
M.A. Malone, 650-723-6912 (Broadcast Media)
mamalone@stanford.edu

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