Nomadic Outposts Of Transplanted Stem Cells Tracked In Stanford Study
Public release date: 15-Dec-2003

Contact: Mitzi Baker
650-725-2106
Stanford University Medical Center

Nomadic outposts of transplanted stem cells tracked in Stanford study

STANFORD, Calif. - Doctors regularly inject stem cells into patients whose bone marrow has been destroyed by
chemotherapy or radiation, but they haven't known where these cells go after being injected. Research at the Stanford
University School of Medicine has yielded an unexpected answer: when injected into mice, these cells may set up camp in
one tissue early on but then move to another location or disappear entirely.

Published in the Dec. 15 online edition of the Proceedings of the National Academies of Science, the work upsets
current thinking that transplanted stem cells find a habitable niche, settle in for the long haul and begin producing
new blood cells. Instead, the newly transplanted cells drift throughout the body, nestling in one of a few homes where
their populations subsequently wax and wane until some finally flourish.

Researchers said the procedure used to follow the injected cells' movements could one day help scientists hone their
techniques for transplanting bone-marrow stem cells in humans and optimize therapies for cancer and immunodeficiencies.
Developing these types of new stem cell-based treatments for cancer is among the primary goals of Stanford's Institute
for Cancer/Stem Cell Biology and Medicine.

Yu-An Cao, PhD, a research associate and first author of the paper, said that until now injecting bone-marrow stem
cells into a patient was like injecting them into a black box. "We didn't know where those cells were going," he said.
Watching the fates of these cells after transplantation had raised more questions than it answered. He said in testing
a new protocol, they now can watch to see whether the cells proliferate more quickly or if the patterns of inhabitation
are altered.

"We are really curious about what is happening," Cao said. "We want to know why the process is so dynamic with
unpredictable fates for the initial stem cell foci. There's no obvious reason for the stem cells to leave what appears
to be a perfectly good place to homestead and proliferate."

Eventually, the work also could help guide transplantation procedures using other types of stem cells. Cao said an
upcoming experiment will use the same technique to monitor transplanted neuronal stem cells. "We can monitor the fate
of those stem cells and help evaluate transplantation protocols," he said. This type of approach could speed the
development of stem cell transplantation therapies for disorders such as Parkinson's disease.

Cao and Christopher Contag, PhD, assistant professor of pediatrics, radiology, microbiology and immunology, and lead
author of the paper, were able to follow the transplanted cells' travels because they all made a firefly protein called
luciferase. This protein produces a dim light when it comes in contact with another molecule called luciferin. Unlike
fireflies, mice don't normally make luciferin, but the recipient mice received doses of the molecule throughout the
experiment. Once injected into the recipient mice - whose bone marrow had been destroyed by radiation - the luciferase-
producing transplanted cells produced a faint glow. Like a campfire at a new settlement, this dim light pinpointed the
cells' location.

Although the light from luciferase isn't bright enough to see by eye, an ultrasensitive video camera originally
developed by Contag can detect the faint light and show researchers where the glowing cells have settled. The
experiment highlighted a handful of stem cell resting places, including the spleen and the bone marrow in the
vertebrae, thighbone, shinbone, skull, ribs and sternum, where stem cells were already known to produce new blood
cells.

Of all the locations, the spleen and the vertebrae were the two most likely sites for the new cells to settle. These
are also the two roomiest compartments, according to Contag. "Where the cells go initially seems to relate to the size
of the compartment and its openness," he said. If that location contained existing stem cells, the transplanted stem
cell would detect signals indicating, "this compartment is full, we don't want you here," he added. An empty
compartment probably lacks these unwelcoming signals. "The cell knows there's an empty seat to jump into, and now we
can watch them play musical chairs - we just don't hear the music yet."

What surprised the researchers is how much the pattern varied. In many cases one location would initially house a
healthy population of glowing stem cells, only to have that population fade over time while daughter cells set up camp
at a distant location. In other mice, locations that initially contained a languishing population of cells would
suddenly flourish. When the researchers took stem cells from sites within one transplanted animal and put them into a
second mouse lacking bone marrow, those stem cells once again seemed to take a random path to new niches and started
the game of musical chairs over again. "This shows that the niche preferences aren't programmed into the cells," Contag
said.

Other Stanford researchers who contributed the work include postdoctoral scholars Amy Wagers, PhD, and Andreas
Beilhack, PhD; technician Joan Dusich; research associate Michael Bachmann, MD, DSc; Robert Negrin, MD, associate
professor of medicine; and Irving Weissman, MD, the Karel and Avice Beekhuis Professor of Cancer Biology and director
of Stanford's Institute for Cancer/Stem Cell Biology and Medicine.

Contag is one of the founders of Xenogen, which makes the sensitive video camera used in this study.

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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

PRINT MEDIA CONTACT: Mitzi Baker at 650-725-2106 ([log in to unmask])

BROADCAST MEDIA CONTACT: M.A. Malone at 650-723-6912 ([log in to unmask])

SOURCE: EurekAlert, DC
http://www.eurekalert.org/pub_releases/2003-12/sumc-noo121503.php

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