Immune system modulation can halt liver
failure in animals
Mass. General researchers
report new approach that may allow organ to regenerate
BOSTON - September 25, 2007 - Massachusetts General Hospital
(MGH) researchers have a developed a totally new approach to treating
liver failure - manipulating the immune response. If the results
of the animal study can be applied in human patients, the approach
may be able to keep patients alive until donor organs become available
or to support liver function until the organ can regenerate itself,
eliminating the need for a transplant. The findings are being reported
in the journal PLOS One.
"We have identified a non-hepatic source of cells that can
easily be expanded to the scale required for clinical application,"
says Martin Yarmush, MD, PhD, director of the Center
for Engineering in Medicine at MGH, the paper's senior author.
He also is the Helen Andrus Benedict Professor of Surgery and Bioengineering
in the Harvard-MIT Division of Health Science and Technology (HST)
and a senior scientific staff member at the Boston Shriners Burns
The liver is one of the few major organs that is able to regenerate
itself. But when the organ is damaged by diseases like chronic hepatitis,
long-term alcohol consumption, or other causes, ongoing inflammation
can increase cell death and suppress the natural regenerative process.
The only current treatment for end-stage liver failure is transplantation,
which is limited by the organ supply and requires long-term immunosuppressive
treatment. While external liver assist devices have successfully
supported some patients, such machines require a supply of preferably
human liver cells, which have been difficult to acquire and expand.
For their investigation, the MGH research team used mesenchymal
stem cells (MSCs) - cells from the bone marrow that develop into
tissues supporting blood cell development in the marrow cavity.
Previous research has shown that MSCs are able to inhibit several
immune system activities. A supply of MSCs can be extracted from
a patient's own marrow and expanded to levels that could be therapeutically
useful. To evaluate the ability of human MSCs to treat organ failure
involving inflammatory activity, the investigators tested several
ways of using the cells to treat rats in which liver failure had
Several approaches to administering MSCs reduced the biological
signs of liver failure and improved the animals' survival. Although
simply transplanting MSCs was not effective, two methods of delivering
molecules secreted by the cells lessened inflammation within the
liver and halted cell death. Cycling the blood of rats with liver
failure through an external bioreactor containing MSCs also greatly
reduced the metabolic signs of liver failure in the animals. Even
more significantly, 71 percent of the rats treated with the MSC-seeded
bioreactor survived, while only 14 percent of those in a control
group were alive one week later.
"One essential function of MSCs in the bone marrow is to secrete
molecules that promote the growth and maturation of blood cells,"
say co-lead author Biju Parekkadan, an HST graduate student working
in Yarmush's lab. "We are now finding that these same molecules
can be used as potent immunotherapeutics and envision a multi-tiered
treatment of liver failure based on this work. A patient presenting
with liver failure could first be treated with an intravenous injection
of an 'off-the-shelf' drug containing MSC-produced factors in an
effort to halt cell damage and allow the organ to regenerate. If
that is not effective, an MSC-based support device could be used
as a bridge to transplantation or even as a long-term treatment."
The researchers note that exactly how MSC-produced molecules inhibit
the movement of immune cells into a damaged organ is not yet known
and is currently under investigation. They also hope to examine
the possibility of combining both MSCs and liver cells in a potential
support device and to test the potential of MSCs to treat other
Additional co-authors of the PLOS ONE paper - all investigators
in the MGH Center for Engineering in Medicine - are co-lead authors
Daan van Poll, MD, and Kazuhiro Saganuma, MD; and co-authors Edward
Carter, Francois Berthiaume, PhD, and Arno Tilles, MD. The work
was supported by grants from the National Institutes of Health,
Shriners Hospitals for Children, the National Science Foundation
and the Michael van Vlooten Foundation.
Massachusetts General Hospital, established in 1811, is the original
and largest teaching hospital of Harvard Medical School. The MGH
conducts the largest hospital-based research program in the United
States, with an annual research budget of more than $500 million
and major research centers in AIDS, cardiovascular research, cancer,
computational and integrative biology, cutaneous biology, human
genetics, medical imaging, neurodegenerative disorders, regenerative
medicine, systems biology, transplantation biology and photomedicine.
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