Hepatitis C is a viral disease that leads to inflammation and organ failure. However, researchers are puzzled as to why some individuals are very susceptible to the disease, while others are not.
Researchers believe they could find out how genetic variations produce these different responses by investigating liver cells from different individuals in the lab. However, liver cells are hard to obtain and extremely challenging to grow in a lab dish as they often lose their normal function and structure when removed from the body.
Now, scientists from MIT, Rockefeller University and the Medical College of Wisconsin have found a technique to generate liver-like cells from induced pluripotent stem cells (iPSCs). iPSCs are created from body tissues instead of embryos; the liver-like cells that can be infected with hepatitis C. iPSCs could allow researchers to investigate why individuals respond differently to the disease. The study is published in the Proceedings of the National Academy of Sciences.
Although many research terms have tried to established an infection in cells obtained from iPSCs, this study is the first to have done so. In addition, the new technique could eventually facilitate “personalized medicine.” Using tissues obtained from the patient being treated, doctors could test the effectiveness of various medications and customize a treatment for that individual patient.
This study is a joint effort between Sangeeta Bhatia, the John and Dorothy Wilson Professor of Health Sciences and Technology and Electrical Engineering and Computer Science at MIT; Charles Rice, a professor of virology at Rockefeller; and Stephen Duncan, a professor of human and molecular genetics at the Medical College of Wisconsin.
In 2011, Bhatia and Rice revealed that by growing liver cells on special micropatterned plates that direct their organization, they could influence the cells to grow outside the body. Although, these cells can be infected with hepatitis C, researchers cannot proactively research the role of genetic variation in viral responses, as the cells derive from organs donated for transplantation and represent only a small population.
Bhatia and Rice collaborated with Duncan, who had demonstrated that he could transform iPSCs into liver-like cells, in order to produce cells with more genetic variation.
Often, such iPSCs are taken from skin cells. Researchers can restore these cells to an immature state – the same as embryonic stem cells – which can differentiate into any cell type by switching on specific genes in those cells. The cells can then be directed, once they become pluripotent, to become liver-like cells by switching on genes that regulate liver development.
In this study, MIT postdoc Robert Schwartz and graduate student Kartik Trehan infected those liver-like cells with hepatitis C. They created the viruses to expel a light-producing protein each time they went through their life cycle in order to confirm that infection had taken place.
The primary goal for the team is to obtain cells from individuals who had unusual reactions to hepatitis C infection and transform them into liver cells in order to research their genetics to find out why they responded the way they did.
“Hepatitis C virus causes an unusually robust infection in some people, while others are very good at clearing it. It’s not yet known why those differences exist.”
One possible reason may be genetic variations in the expression of immune molecules, such as interleukin-28, a protein that has been demonstrated to play a vital role in the response to hepatitis infection. Other potential factors include, cell’s susceptibility to having viruses control their replication machinery and other cellular structures, as well as cell’s expression of surface proteins that allow the virus to penetrate the cells.
Bhatia explains the liver-like cells generated in this investigation are similar to “late fetal” liver cells. The team is currently working on producing more mature liver cells.
The long-term goal for the team is personalized treatments for individuals with hepatitis. According to Bhatia one could imagine obtaining cells from an individual, making iPSCs, reprogramming them into liver cells and infecting them with the same strain of hepatitis that the individual has. This would allow doctors to test various medications on the cells to find out which ones are better at clearing the infection.
Written by Grace Rattue