Researchers at the Stanford University School of Medicine have developed a way to quickly and efficiently convert human fat stem cells into liver cells.
Scientists at the Peltz lab obtained human fat cells through liposuction, isolating the fat stem cells known as adipocyte stem cells, and through a method called spherical culture, induced these cells to become liver cells, or spherical-culture induced hepatocytes (SCi-Heps). They then administered these hepatocytes in a mouse model organism and showed that these liver cells were able to reconstitute functioning human liver.
“There is a lot of potential for [treating] different liver diseases,” said Dan Xu M.S. ‘97, a postdoctoral fellow at Stanford, and the lead author of the study.
The Peltz lab’s method solves the problems that come with creating liver cells through previously established procedures such as the use of induced pluripotent stem (iPS) cells. In addition to having only a 10 percent yield rate, iPS requires 30 or more days to produce liver cells and can cause tumor formation.
This new technique, however, does not involve any animal products or introduce any foreign genes and shows no evidence of tumor formation.
“We’re now up to 60-80 percent [yield] and the timeframe is down to nine days,” said Gary Peltz M.D. ‘85 Ph.D. ‘85, professor of anesthesia and the paper’s senior author. “And we’re getting 15-20 fold more cells than we use to get. So all this puts us within a scale that is appropriate for human use.”
Another advantage to this method is the wide availability of fat.
“Unfortunately here in America fat is readily available,” Peltz said. “There’s plenty of fat to go around, and through liposuction, you have a minimally invasive way to obtain a large number of cells in order to [produce liver cells for use in humans].”
Through this method, the Peltz lab hopes to break ground in treating acute toxic insults like drug overdoses and mushroom poisoning.
“We hope, by some time in 2015, to be able to test whether this will work in humans,” Peltz said. “Our target right now is Tylenol induced liver toxicity. People who take an overdose of Tylenol basically destroy their liver and we hope to be able to replace it using this method—[using] the same exact procedures we use in the mice.”
People with acute toxic insults like Tylenol induced liver toxicity need a liver transplant within two to three weeks, Peltz said. But there are ten times more people needing a liver than there are livers available. Even if a liver is found, recipients must take immunosuppressants—a class of drugs that reduces the strength of the body’s immune system—for the rest of their lives to cope with the body’s rejection of the new liver.
But if a patient’s liver is regenerated through the Peltz lab’s technique, those side effects may be avoided.
“With [our] procedure you do relatively minor things,” Peltz said. “You do a liposuction and then a needle injection into the liver. There is no major surgery, and since it’s your own cells you won’t need immunosuppression.”
However, before the researchers can use these cells in humans, they must assure that the liver cells are safe.
The researchers performed careful comparisons to see how closely SCi-Heps resemble liver cells. They looked at the functional properties of liver cells, such as metabolizing drugs, making the necessary proteins and taking in lipids or LDL.
The researchers also did a detailed microarray analysis of gene expression that looked at 30,000 probes and compared the induced hepatocytes they made to liver cells and fat cells. The analysis suggested that the hepatocytes produced through this technique have 80-90 percent resemblance to human liver cells.
“We have to do a lot of tests based on the FDA guidelines,” Xu said. “They gave us 30 pages that we have to follow.”
“The next step is to make sure the cells we inject in human beings do not have any safety issues, meaning there is no tumor formation, and [the liver cells] won’t cause extra toxicity,” Xu added.
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