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November 25, 2005
Regenerating Worms Help Elucidate Stem Cell Biology
Specimens of the clonal strain CIW4 of the planarian Schmidtea mediterranea. These animals are excellent tissue regenerators and share with humans bilateral symmetry and tissues derived from all three germ layers, i.e., ectoderm, mesoderm and endoderm.
Using a tiny flatworm best known for its extraordinary ability to
regenerate lost tissue, researchers have identified a gene that
controls the ability of stem cells to differentiate into specialized
cells. The gene encodes a protein that is most similar to the protein
PIWI, an important regulator of stem cells in organisms ranging from
plants to humans.
The replacement of tissue lost to injury or shed during the body's
normal activities is essential for the survival of most organisms. The
new study, published in the November 25, 2005, issue of the journal
Science, helps scientists understand how stem cells make this
process possible. The research, performed at the University of Utah
School of Medicine, was carried out by Helen Hay Whitney postdoctoral
fellow Peter W. Reddien (now an Associate Member at the Whitehead
Institute for Biomedical Research), and led by Howard Hughes Medical
Institute investigator Alejandro Sánchez Alvarado.
“This encompasses millions of years of evolution. Still, we don’t know exactly how this particular gene is doing its function in any of these organisms.”
Alejandro Sanchez Alvarado
Salamanders, zebrafish, and other organisms are capable of
regenerating entirely new body parts. Although the human body does not
face such demands, it is constantly replacing lost cells. For example,
blood replenishes itself, wounds heal, and the lining of the gut
sloughs off and is restored. Nowhere, however, is the process of
regeneration more dramatic than in the freshwater flatworm planaria.
Cut one of these animals in half, and a week later, two fully
functional worms will have developed from the pieces. Cut a piece that
is 1/279th the size of the animal, and it too will regrow
into a complete worm.
The process, scientists know, is dependent on stem cells in the
adult planaria known as neoblasts. Like all stem cells, neoblasts have
the capability to develop into a variety of different cell types,
meaning they can transform themselves into whatever tissue is needed
after injury, be it intestine, skin, or brain. Even in the absence of
injury, these cells are critical to maintain a healthy worm, as they
are also responsible for replacing tissue that has been lost naturally.
Scientists are just beginning to explore the molecular mechanisms that
control adult stem cells, so, said Sánchez Alvarado, it's too
soon to know how similar these mechanism are in planaria neoblasts and
other organisms' stem cells. “But at least at the gross
morphological level and gross biological functions, they compare quite
well,” he said.
Destruction of a planarian's neoblasts, which occurs when scientists
expose the animal to radiation in the laboratory, is devastating.
“The animal will survive on the virtue of its differentiated
cells,” Sánchez Alvarado said, “but as the tissues
begin to turn over and there are no stem cells to replace such tissues,
the animal begins, basically, to fall apart.” It degenerates in a
very specific way, he explained, with the tip of the head beginning to
regress, followed by a curling up of the sides of the body. Not
surprisingly, worms without neoblasts also lose their ability to
regenerate.
With their unparalleled capacity for regeneration and the many
environmental cues that influence the division and differentiation of
their neoblasts, Sánchez Alvarado considers planaria an
excellent model to tease out the intricacies of adult stem cell
biology. “I think they probably have a lot to teach us about how
a population of stem cells is being regulated in vivo, rather
than in a Petri dish,” he said. So Sánchez Alvarado and
his colleagues set out to understand exactly how neoblasts carry out
the remarkable maintenance and recreation of the varied tissues that
make up a flatworm.
Earlier this year, they got their first clues when they individually
turned off 1,065 of the worm's genes, and found 240 that were involved
in some aspect of regeneration. Importantly, Sánchez Alvarado
noted, 85 percent of these genes are found in the genomes of other
organisms, including humans. In the current study, the scientists
zeroed in on one of these genes, called smedwi-2, that was
active in dividing neoblasts.
Smedwi-2 belongs to the Argonaute/PIWI protein family
and is most similar to PIWI proteins found in fruit flies. According to
Sánchez Alvarado, PIWI proteins have been shown to play a
role in regulating stem cells in plants and fruit flies, as well as
humans. “This encompasses millions of years of evolution,”
he said. “Still, we don't know exactly how this particular gene
is doing its function in any of these organisms.”
To find out, the scientists used a technique known as RNA
interference to specifically turn off the piwi gene in planaria.
When they did this, they found that worms had the same defects as those
whose neoblasts have been destroyed by radiation — head regression,
curling, and the inability to regenerate — suggesting that the gene
was needed for normal neoblast function.
The researchers examined piwi's role more closely, and found
that when they amputated part of a worm where the gene had been turned
off, the stem cells were still able to detect the wound. Amputation
triggered the stem cells to divide, as in normal worms, and the
daughter cells traveled proficiently to the part of the body where they
were needed. However, once they arrived, they failed to replace the
lost tissue.
When neoblasts divide, they produce at least two cell types - one
copy of the original, and one cell that can develop into a specialized
cell to replace a lost cell elsewhere in the body. The researchers
found that without piwi, the daughter cells from this division
failed to differentiate into a specialized cell once they'd reached
their destination. Based on their findings, Sánchez Alvarado
said, “We think that piwi is actually involved in
producing daughter cells that are competent to restore aged
differentiated cells during homeostasis as well as missing tissues
after amputation. Unlike what's been thought about piwi for some
time, which is that it was required to maintain the stem cell, we think
that's not happening here. The stem cells are being maintained by
another mechanism, and it's the division progeny, instead, that is
being affected.”
There's some evidence, Sánchez Alvarado said, that
piwi plays a similar role in regulating the progeny of adult
stem cells in humans. He cautioned that more work is needed to
determine just how functionally similar the factors regulating stem
cells in planaria are to those in higher organisms. But so far there's
good evidence that many of the important genes are the same, he said.
And the current study begins the detailed analysis that will be needed
to establish whether this humble worm can illuminate the mechanisms
underlying the unique biology of stem cells.
Image: A. Sánchez Alvarado
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Versión en español
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Jim Keeley
