Stem Cell as Hepatitis Cure? Bhatia, Rice, & Duncan Research

To crack the Hepatitis C puzzle, scientists create new liver-like cells. Scientists from three separate institutions have teamed up to create liver-like cells that will allow them to study why people respond differently to hepatitis C, a contagious liver disease that can lead to cirrhosis of the liver and liver cancer and organ failure.

According to the World Health Organization, about 130–170 million people are chronically infected with the hepatitis C virus, and more than 350,000 people die from hepatitis C-related liver diseases each year.

Hepatitis C affects people differently — in some, it’s a mild illness that lasts a few weeks; in others, it develops into a lifelong condition that leads to liver inflammation and death. But why some people are very susceptible to the infection, while others are resistant — that remains a puzzle.

One possible explanation is genetic differences in the expression of immune molecules like interleukin-28, a protein that plays an important role in the response to hepatitis infection.

Another possible factor is a genetic difference in the expression of surface proteins in cells that enable the virus to enter the cells. Or, genetic differences that cause differing susceptibility of cells to having viruses take over their replication machinery and other cellular structures.

But scientists today are still unsure about these. And in order to develop better ways to prevent and treat hepatitis C, scientists need to solve this mystery.

If researchers could study liver cells from different people in the lab, they could determine how genetic differences produce these varying responses.

But liver cells are difficult to obtain and very difficult to grow in a lab dish—when removed from the body, they tend to lose their normal structure and function.

Working to crack this puzzle, researchers from the Massachusetts Institute of Technology, Rockefeller University and the Medical College of Wisconsin have developed a way to create liver-like cells from induced pluripotent stem cells, or iPSCs.

iPSCs are derived from normal body tissues of adults, often skin cells. They aren’t taken from embryos. By genetically reprogramming them or “switching on” certain genes in those adult cells, scientists can revert them to an embryonic stem cell–like state that can differentiate into any cell type.

Once the cells become pluripotent, scientists directed them to become liver-like cells by turning on genes that control liver development.

What Hepatitis C-infected cells mean
The new liver-like cells induced from iPSCs were now infected with hepatitis C. To confirm that infection had occurred, the researchers engineered the viruses to secrete a light-producing protein every time they went through their life cycle.

The researchers claim this is the first time an infection has been made in cells derived from iPSCs. The infected liver-like cells, they say, can now be studied by scientists to find out why people respond differently to the infection.

According to them, their technique may also eventually enable personalized medicine — in the future, doctors can test the effect different drugs have on tissues derived from the patient being treated and then customize therapy for that patient.

The new study is a collaboration between Sangeeta Bhatia, MIT’s John and Dorothy Wilson Professor of Health Sciences and Technology and Electrical Engineering and Computer Science; Charles Rice, a professor of virology at Rockefeller; and Stephen Duncan, a professor of human and molecular genetics at the Medical College of Wisconsin.

Their new technique is described in the Jan. 30 issue of the Proceedings of the National Academy of Sciences.

“This is a very valuable paper because it has never been shown that viral infection is possible” in cells derived from iPSCs, says Karl-Dimiter Bissig, an assistant professor of molecular and cellular biology at Baylor College of Medicine.

Bissig, who was not involved in this study, adds that the next step is to show that the cells can become infected with hepatitis C strains other than the one used in this study, which is a rare strain found in Japan. Bhatia’s team is now working toward that goal.

From liver cells to liver-like cells
Working together last year, Bhatia and Rice induced liver cells to grow outside the body by growing them on special micropatterned plates that direct their organization.

These liver cells can be infected with hepatitis C, but could not used to study the role of genetic variation in viral responses proactively, as the cells represented only a small genetic population, coming from a few organs donated for transplants.

To make cells with more genetic variation, Bhatia and Rice decided to team up with Duncan, who had previously shown that he could transform iPSCs into liver-like cells.

In the current paper, the researchers took the next step, and infected the liver-like cells with hepatitis C.

Eventually, the researchers plan to take skin cells from patients who had unusual reactions to hepatitis C infection, transform those into liver cells and study their genetics to see why they responded to the disease the way they did. Right now, the liver-like cells created by Bhatia’s team are comparable to “late fetal” liver cells, so the researchers are also working on generating more mature liver cells.

Finally, as a long-term goal, the researchers are aiming for personalized treatments for hepatitis patients.