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Mini-livers on a chip | Eurek alert!

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image: Researchers from the Gladstone Institutes have designed a new platform to study how the human immune system responds to hepatitis C infection by combining microfluidic technology with liver organoids.
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Credit: Photo: Michael Short/Gladstone Institutes

SAN FRANCISCO, CA—April 6, 2022—A hepatitis C vaccine has eluded scientists for more than 30 years, for several reasons. For one thing, the virus that causes the disease comes in many genetic forms, making it difficult to create a broadly effective vaccine. On the other hand, the study of hepatitis C has been difficult because the options in animals are limited and the laboratory methods using infected cells have not sufficiently reflected the real dynamics of the infection.

Now, researchers from the Gladstone Institutes have developed a new platform to study how the human immune system responds to hepatitis C infection. The method, featured in the scientific journal Open Biology, marries microfluidic technology (which allows scientists to precisely manipulate fluids on a microscopic scale) with liver organoids (clumps of three-dimensional cells that mimic the biology of real human livers).

“The 3D structure and cellular composition of liver organoids allows us to study viral entry and replication in a very physiologically relevant way,” says Gladstone Senior Investigator Todd McDevitt, PhD, a senior author of the new study.

“Our approach allows for a more controlled and precise investigation of the immune response to hepatitis C infection,” says Melanie Ott, MD, PhD, director of the Gladstone Institute of Virology and another lead author of the study. “We hope our method will accelerate the discovery of a much-needed vaccine.”

Recreate the interaction between liver and immune cells

The hepatitis C virus targets the liver. After the initial infection, some people recover with few or no symptoms, but others have a lifelong infection that can lead to serious liver disease. Medicines can successfully treat hepatitis C, but may be difficult to access or afford, and a person who has been treated may become reinfected later.

“An effective vaccine would train the immune system and prevent reinfection with one of the most common forms of the virus,” says Camille Simoneau, PhD, the study’s co-lead author and postdoctoral researcher in Ott’s lab. “It would have enormous public health benefits around the world.”

To develop such a vaccine, scientists need detailed knowledge of how the liver interacts with the hepatitis C virus and the immune system, in particular immune system T cells. However, it has proven quite difficult to get individual liver cells to interact with the virus in a way that realistically mirrors what might be happening in an infected person’s body.

In recent years, thanks in large part to advances made by McDevitt and other Gladstone researchers, 3D liver organoids have emerged to provide new, more biologically realistic opportunities to study the interaction between liver cells, the virus of the hepatitis C and T cells. Yet the challenges persisted.

“So far, we’ve observed these interactions in relatively large fluid droplets,” says Vaishaali Natarajan, PhD, study co-lead author and former Gladstone postdoctoral fellow in McDevitt’s lab. “But it’s difficult to track individual organoids in the droplets, which limits what we can learn from them.”

So the researchers decided to move the whole system onto a microfluidic chip, a device with a network of tiny channels that allows precise control of the positioning of the organoids and allows researchers to better observe their interaction with their environment.

In the new system, liver organoids from adult stem cells are embedded at fixed positions in channels on the chip. Meanwhile, fluid-suspended T cells are able to move freely through the channels and interact with organoids, similar to the movement of blood-borne T cells in true liver tissue. Because the organoids are fixed in place, researchers can monitor them and T cells over time using standard microscopy techniques.

“For the first time, we can closely observe these cellular interactions in a laboratory environment in a way that is biologically more faithful to the tissues involved in hepatitis C infection,” says Ott.

Preparing the ground for discovery

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

So they cultured liver organoids and exposed them to a specific molecule found in the hepatitis C virus. After exposure, the organoid cells presented this molecule on their surface, as they would after an infection. The researchers then integrated the organoids into a microfluidic chip and introduced T cells into their environment.

These T cells, developed by Ann Erickson in lead author Stewart Cooper’s lab at the California Pacific Medical Center Research Institute, were trained to recognize the molecule on the surface of organoids.

Sure enough, the T cells detected the organoid cells that presented the viral molecule and traveled through the microfluidic channels to kill them, just as they could target and kill infected cells in the body to fight hepatitis C.

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

“Our study suggests that our approach could be used to identify and study other viral molecules that elicit strong immune responses and have the potential to form the basis of new vaccines,” McDevitt says. “I’m excited to see where this combination of organoids and microfluidics will lead next.”

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About the study

The paper “Modeling T cell immunity against hepatitis C virus with liver organoids in a microfluidic coculture system” was published by Open biologya journal of the Royal Society, March 2, 2022.

Other authors are Nathan Meyers of Gladstone and Jody Baron of UC San Francisco.

The work was supported by the National Institutes of Health (grants R01 AI097552-01A1, DP1D A038043-01, and RO1 DK064051), the Technical Training Foundation, the Ibrahim El-Hefni Liver Biorepository, and the Raab Foundation.

About Gladstone Institutes

For our work to do the greatest good, Gladstone Institutes focuses on conditions with profound medical, economic and social impact – unresolved diseases. Gladstone is an independent, not-for-profit life science research organization that uses visionary science and technology to defeat disease. It has an academic affiliation with the University of California, San Francisco.