Mini Liver on a Chip

For more than 30 years, scientists have been unable to develop a hepatitis C vaccine for several reasons

Now, researchers at the Gladstone Institutes have developed a new platform for studying the human immune system's response to hepatitis C infection

"The 3D structure and cellular composition of liver organoids allows us to study viral entry and replication in a highly correlated physiological manner," said Gladstone senior investigator Todd McDevitt, Ph.

The study's other senior author, Melanie Ott, MD, director of the Gladstone Institute of Virology, said: "Our method enables a more controlled and accurate investigation of the immune response to hepatitis C infection

They have developed a new platform that could help speed up the search for a hepatitis C vaccine

Rebuild interactions between liver and immune cells

The hepatitis C virus targets the liver

"A successful vaccine would train the immune system and prevent reinfection with any of the most common forms of the virus," said study co-first author Camille Simoneau, PhD, a postdoctoral researcher in Ott's lab

To develop such a vaccine, scientists need a detailed understanding of how the liver interacts with the hepatitis C virus and the immune system, particularly the immune system's T cells

"For the first time, we can closely observe cellular interactions in tissues involved in HCV infection in a more realistic biological way in a laboratory setting

In recent years, thanks in large part to advances by researchers at McDevitt and Gladstone, the emergence of 3D liver organoids has provided a new, more realistic way to study the interactions between hepatocytes, hepatitis C virus, and T cells.

"So far, we've been looking at these interactions in relatively large droplets," said study co-first author Vaishaali Natarajan, Ph.

So the researchers decided to move the entire system onto a microfluidic chip, a device with a network of tiny channels that can precisely control the position of the organoids and allow researchers to better observe how they interact with their surroundings role

In the new system, liver organoids grown from adult stem cells are embedded in fixed locations in the chip channel

"For the first time, we can closely observe these cell interactions in a laboratory setting in a way that is biologically more suitable for tissues involved in HCV infection," Ott said

Setting the stage for discovery

To demonstrate the promise of their new system, the researchers first wanted to confirm that it could mimic the recognition of infected liver cells by T cells

So they grew liver organoids and exposed them to a specific molecule found in the hepatitis C virus

The T cells, developed by Ann Erickson of the California Pacific Medical Center Research Institute in senior author Stewart Cooper's lab, were trained to recognize molecules on the surface of organoids
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Sure enough, the T cells detected the organoid cells presenting the viral molecules and killed them through the microfluidic channel -- just as they target and kill infected cells in the body to fight hepatitis
C.

Since researchers can precisely alter the microfluidic environment by adding or removing substances, the platform can also be used to explore many other aspects of hepatitis C infection in unprecedented detail
.

"Our study shows that our method can be used to identify and study other viral molecules that elicit strong immune responses, and could potentially form the basis for new vaccines," McDevitt said
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The combination will lead the future
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