U-M Team Determines Defective Stem Cells Cause Rare
Intestinal Disorder
Hirschsprung's disease — a serious, sometimes life threatening, genetic disorder
affecting one in 5,000 newborn infants — is caused by defective stem cells,
according to new research by Medical School scientists.
Sean Morrison, Genevieve Kruger and Tashihide Iwashita Photo: Martin Vloet |
Scientists know that Hirschsprung's is a genetic disease, and they have identified
some of the mutations associated with the disorder. But no one knew exactly
how these mutations affected the development of the intestinal nervous system.
Based on new research, U-M scientists now say the basic problem is that neural
crest stem cells, which give rise to nerves in the embryonic digestive system,
never reach the lower part of the developing gut.
Babies with Hirschsprung's disease are born without ganglion cells — specialized
nerve cells in the large intestine, which trigger contractions to eliminate
feces. The result is chronic constipation and intestinal obstructions requiring
surgery, sometimes immediately after birth.
"We found that the mutated genes causing Hirschsprung's disease act in neural
crest stem cells to impair their ability to form a normal intestinal nervous
system," says Sean J. Morrison, Ph.D., a Howard Hughes Medical Institute investigator
and assistant professor of internal medicine in the U-M Medical School.
Neural cells grown from a single neural crest stem
cell Photo: Genevieve Kruger |
Neural crest stem cells are one variety of "adult" stem cells. Unlike embryonic
stem cells, which can become nearly any cell in the body, neural crest stem
cells normally develop into the neurons and supporting cells of the peripheral
nervous system — as well as connective tissues, such as dermis, bone and vascular
smooth muscle. They first show up in the embryo's primitive neural tube, which
forms the spinal cord. When everything goes right, neural crest stem cells
then migrate through the developing gut, seeding the primitive digestive system
with stem cells capable of generating a healthy, functioning intestinal nervous
system.
But in embryos with Hirschsprung's disease, some or all of these stem cells
get stuck and never migrate past the esophagus. U-M scientists say mutations
in a gene called Ret are responsible for the cells' inability to move past
the esophagus into the stomach and intestines of the developing embryo.
The study was funded by the Howard Hughes Medical Institute, the National
Institutes of Health, the Searle Scholars Program and the U-M's Institute of
Gerontology. Ricardo Pardal, Ph.D., a U-M research fellow, and Mark J. Kiel,
a graduate student in the U-M Medical School 's M.D./Ph.D. program, were collaborators
in the study.
-SFP
For an expanded version of the story:
www.med.umich.edu/opm/newspage/2003/hirschsprung.htm
Learn more about Hirschsprung's disease click
here.
 
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