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A combination of bioengineering and medical research at the University
of California, San Diego has led to a new discovery that could pave the
way for more effective treatments for liver disease.
In this work, the researchers have utilized an array system that can
identify the biological components that can lead to or alleviate liver
disease. The technology works by controlling the range of environments
surrounding star-shaped liver cells called hepatic stellate cells
(HSCs). HSCs are the major cell type involved in liver fibrosis, which
is the formation of scar tissue in response to liver damage. The
activated stellate cell is responsible for secreting collagen that
produces a fibrous scar, which can lead to cirrhosis.
Current approaches to identify the factors affecting HSC biology
typically focus on each factor individually, ignoring the complex
cross-talk between the many components acting on the cells. The
high-throughput cellular array technology developed by UCSD researchers
systematically assesses and probes the complex relationships between
hepatic stellate cells and components of their microenvironment. By
doing this, they found that certain proteins are critical in regulating
HSC activation and that the proteins influence one another's actions on
the cells. The findings were published in the September 2009 issue of Integrative Biology.
"We can spot hundreds of combinations of proteins in the matrix
surrounding the cell such as different kinds of collagen – you can spot
them individually and in combination, so you can get hundreds of
combinations with several proteins," said Shu Chien, co-author of the
paper and bioengineering professor and director of the Institute of
Engineering Medicine at UCSD. "We used a spotting pin that's normally
used for microarray DNA spotting. But we spot proteins instead of DNA
"In one step we can look at the physical and chemical
micro-environment of the cells," Chien added. "Now we can look at the
optimum condition that is best for the cells to proliferate and
The high-throughput cellular array technology used in this research
was developed by Chien and his lab colleagues a few years ago mainly
for stem cell research, but it has not been applied to this type of
research before involving hepatic stellate cells.
"Our lab is interested in the cells that are responsible for laying
down the fibrous scar in all types of chronic liver disease," said Dr.
David Brenner, the dean of the UCSD School of Medicine and co-author of
the paper. "In the course of 20 years, people have tried three or four
matrixes to try to optimize their growth. Shu Chien mentioned this
extracellular matrix array that his lab was using for stem cells, and I
thought it would be an incredible opportunity to understand the effects
of different matrixes in primary cell cultures.
"By looking at the array you get hundreds of different combinations
of proteins and you can look at hundreds of cells at once," Brenner
added. "This will give us new insights for the treatment for liver
fibrosis, and it will give us the platform to test new treatments. This
also allows us to do the critical experiments that will assess the
ability of different drugs to work. There are really no effective
therapies for liver fibrosis—there is only transplantation. Any less
invasive therapy would be desirable. This is a big advance."
Chien said such medical advances are the result of the growing
synergism between engineering and medicine. This study involves the
dissertation work of David Brafman, who received his Ph.D. in
bioengineering from UCSD under the joint advisorship of Chien and
professor Karl Willert of the Department of Cellular and Molecular
Medicine. Chien said the next step for this collaborative effort will
be to develop a platform that allows scientists and researchers to
differentiate cells into the kind they want. It's this type of work,
Chien said, that gives the field of regenerative medicine a boost.
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