Featured Research

from universities, journals, and other organizations

New Chimeric Mouse Model For Human Liver Diseases, Drug Testing

Date:
December 5, 2007
Source:
Salk Institute
Summary:
Cells cultured in the lab are like a fish out of water. Often, their behavior does not reflect their biological function within an entire organ or organism, which, for example, turns studying human liver cells into a big challenge.

Transplanted human liver cells (shown in brown) take hold in the liver and repopulated the host organ over time. The images above show cross sections of mouse liver one month (top), two months (middle), and three months (bottom) after the injection of human hepatocytes.
Credit: Courtesy of Dr. Karl-Dimiter Bissig, Salk Institute for Biological Studies

Cells cultured in the lab are like a fish out of water. Often, their behavior does not reflect their biological function within an entire organ or organism, which, for example, turns studying human liver cells into a big challenge.

One way to get around the altered properties of the stranded cells is to populate mouse livers with human hepatocytes in the hope of creating a natural environment, which is exactly what researchers at the Salk Institute for Biological Studies did. They developed a simple system that allows them to transplant human hepatocytes into immunodeficient mice, which can now be used to test how drugs affect the liver.

"Rodents are often used as model organisms to study the efficacy and toxicity of drugs," says lead author Karl-Dimiter Bissig, M.D. Ph.D., a postdoctoral researcher in the Laboratory of Genetics, "but mouse and rat hepatocytes may function in very different ways when it comes to metabolism of drugs."

In the past, this has led to unexpected toxicity problems, when drugs moved into clinical trials after toxicity tests in rats failed to reveal adverse effects (e.g. Troglitazone). But it also worked the other way around. "The clinical introduction of furosamide, a powerful but perfectly safe diuretic, has been slowed down because of its hepatotoxicity in rats," says Bissig.

The work also holds promise for a better understanding of infectious diseases that affect the liver. "It is basically impossible to grow human hepatocytes in the lab, which was a big hurdle for the study of viruses such as hepatitis A and hepatitis B," says senior author Inder Verma, Ph.D., a professor in the Laboratory of Genetics.

But most importantly, Bissig says, the mice will be an invaluable tool to advance regenerative medicine. "Many inherited disorders affecting liver metabolism could be cured if only five percent of all hepatocytes would express the missing enzyme," he says.

In fact, that's the underlying principle of the Salk researchers' new chimeric mouse. It is based on a murine model for hereditary tyrosinaemia type I, developed by researchers at Oregon Healthy & Science University. An enzymatic defect in the tyrosine catabolism results in a toxic accumulation of byproducts within hepatocytes unless the mice are treated with a drug called NBTC.

Withdrawing the drug allows to selectively expand hepatocytes that do not have this defect, such as transplanted human hepatocytes. Within three months of transplantation, up to 20 percent of the mouse liver is repopulated by human hepatocytes. But what's more, the transplanted cells keep producing a foreign protein slipped inside with the help of a lentiviral vector, the kind usually used for gene therapy. "We are very excited about that aspect since very often cells shut off the production of proteins introduced as part of gene therapy," says Verma.

This research was recently published in the online edition of the Proceedings of the National Academy of Sciences.

Researchers who also contributed to the study include graduate student Tam T. Le and post-doctoral researcher Niels-Bjarne Woods, Ph.D

The research was funded by grants from the National Institutes of Health, the Leducq Foundation, the Ellison Medical Foundation, and the H.N. and Frances C. Berger Foundation.


Story Source:

The above story is based on materials provided by Salk Institute. Note: Materials may be edited for content and length.


Cite This Page:

Salk Institute. "New Chimeric Mouse Model For Human Liver Diseases, Drug Testing." ScienceDaily. ScienceDaily, 5 December 2007. <www.sciencedaily.com/releases/2007/12/071204091921.htm>.
Salk Institute. (2007, December 5). New Chimeric Mouse Model For Human Liver Diseases, Drug Testing. ScienceDaily. Retrieved September 16, 2014 from www.sciencedaily.com/releases/2007/12/071204091921.htm
Salk Institute. "New Chimeric Mouse Model For Human Liver Diseases, Drug Testing." ScienceDaily. www.sciencedaily.com/releases/2007/12/071204091921.htm (accessed September 16, 2014).

Share This



More Plants & Animals News

Tuesday, September 16, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

Some Tobacco Farmers Thrive Amid Challenges

Some Tobacco Farmers Thrive Amid Challenges

AP (Sep. 16, 2014) The South's tobacco country is surviving, and even thriving in some cases, as demand overseas keeps growers in the fields of one of America's oldest cash crops. (Sept. 16) Video provided by AP
Powered by NewsLook.com
Scientists Given Rare Glimpse of 350-Kilo Colossal Squid

Scientists Given Rare Glimpse of 350-Kilo Colossal Squid

AFP (Sep. 16, 2014) Scientists say a female colossal squid weighing an estimated 350 kilograms (770 lbs) and thought to be only the second intact specimen ever found was carrying eggs when discovered in the Antarctic. Duration: 00:47 Video provided by AFP
Powered by NewsLook.com
Raw: Scientists Examine Colossal Squid

Raw: Scientists Examine Colossal Squid

AP (Sep. 16, 2014) Squid experts in New Zealand thawed and examined an unusual catch on Tuesday: a colossal squid. It was captured in Antarctica's remote Ross Sea in December last year and has been frozen for eight months. (Sept. 16) Video provided by AP
Powered by NewsLook.com
Ivorians Abandon Monkey Pets in Fear Over Ebola Virus

Ivorians Abandon Monkey Pets in Fear Over Ebola Virus

AFP (Sep. 16, 2014) Since the arrival of Ebola in Ivory Coast, Ivorians have been abandoning their pets, particularly monkeys, in the fear that they may transmit the virus. Duration: 00:47 Video provided by AFP
Powered by NewsLook.com

Search ScienceDaily

Number of stories in archives: 140,361

Find with keyword(s):
Enter a keyword or phrase to search ScienceDaily for related topics and research stories.

Save/Print:
Share:

Breaking News:
from the past week

In Other News

... from NewsDaily.com

Science News

Health News

    Environment News

      Technology News



      Save/Print:
      Share:

      Free Subscriptions


      Get the latest science news with ScienceDaily's free email newsletters, updated daily and weekly. Or view hourly updated newsfeeds in your RSS reader:

      Get Social & Mobile


      Keep up to date with the latest news from ScienceDaily via social networks and mobile apps:

      Have Feedback?


      Tell us what you think of ScienceDaily -- we welcome both positive and negative comments. Have any problems using the site? Questions?
      Mobile: iPhone Android Web
      Follow: Facebook Twitter Google+
      Subscribe: RSS Feeds Email Newsletters
      Latest Headlines Health & Medicine Mind & Brain Space & Time Matter & Energy Computers & Math Plants & Animals Earth & Climate Fossils & Ruins