The innovation: New 3D organoid model offers insights to biliary atresia pathogenesis
Without prompt treatment, biliary atresia causes bile duct blockages that lead to irreparable liver damage. Researchers at Children’s Medical Center Dallas, part of Children’s Health℠, and UT Southwestern are shedding light on the genesis of biliary atresia, which has clinical onset soon after birth. Using bile duct cells from pediatric patients at Children’s Health, the investigators engineered miniature models of bile ducts, also known as “organoids.” The model is the first to combine multiple cell types, allowing the team to probe the origins of this rare and serious disease.
“This system allows us to investigate communication between different cell types – and see how a breakdown in that process leads to the development of biliary atresia,” says Jorge Bezerra, M.D., Pediatric Hepatologist and Pediatrician-in-Chief at Children’s Health and Professor and Chair at UT Southwestern. “Our findings are pointing us toward new treatments for babies with this disease.”
Why it matters: Engineered models help identify origin of biliary atresia
Biliary atresia is a challenging disease, and it’s been treated the same way since the 1950s. Treatment consists of surgery or the Kasai procedure, which replaces an infant’s damaged bile ducts with a section of intestine. Today, there are still no drugs available to halt the disease because targets for treatment have yet to be identified.
Biliary atresia affects the cholangiocytes, the specialized epithelial cells that line the bile duct. Those cells are typically studied using mouse models or samples of liver tissue from patients. To better study the disease, Children’s Health investigators pioneered the technology to engineer biliary organoids using cells from liver biopsies. Using these organoids, they showed a delay in epithelial function.
“Those studies gave us a snapshot of the disease in time, but we needed a more dynamic model,” says Pranavkumar Shivakumar, Ph.D., Director of the Biliary Atresia Research and Cure Center at UT Southwestern and a leader of the research team.
The team combined patient-derived cholangiocytes with both mesenchymal cells that provide structural support to tissues and endothelial cells that give rise to blood vessels. The tissues organized into a three-dimensional organoid that mimicked the structure and function of the bile duct.
“With this model, we can finally look at cell-specific processes over a period of time to explore how the cells talk with one another and interact with immune cells,” Dr. Shivakumar says.
What to know: Altered crosstalk drives epithelial-mesenchymal transition
Previous research suggested that biliary atresia may be related to a process known as epithelial-mesenchymal transition (EMT), which causes epithelial cells to take on characteristics of mesenchymal cells. As they describe in Nature Communications, the investigators noticed cellular miscues as the process unfolded in their organoid model.
In diseased tissues, an overproduction of a protein called transforming growth factor-β (TGF-β) led to altered crosstalk between neighboring epithelial and mesenchymal cells. That faulty cellular communication caused cholangiocytes to behave like mesenchymal cells, producing molecules that promote fibrosis – a defining feature of biliary atresia.
“The epithelial cells are confused. They don’t know if they’re epithelial or mesenchymal cells,” says Dr. Bezerra. “That confusion leads to a fragmented epithelium and a lack of peribiliary glands that help to repair the epithelium.”
Introducing a compound to suppress TGF-β, however, made a big difference: EMT decreased, peribiliary glands increased, and the rudimentary epithelium began to grow much like those from healthy samples. Next, the team inhibited TGF-β in a mouse model of biliary atresia. “When we treat mice with the TGF-β inhibitor, the ducts open and bile flows,” Dr. Bezerra says. “The animals have much less liver injury, decreased jaundice and increased survival.”
Key findings: From an organoid model to treatment
Dr. Shivakumar continues to study compounds that inhibit TGF-β with an eye toward identifying an existing drug or developing a new one to prevent liver injury in infants with biliary atresia. Because the organoids the team developed can be cryopreserved and reused, they are an important tool for testing new compounds in advance of future human trials.
Meanwhile, researchers at Children’s Health and UT Southwestern are using the models to further study biliary atresia. Such organoids could also be helpful for studying other diseases of the cholangiocytes, including primary sclerosing cholangitis or primary biliary cirrhosis.
The new model – and the clues it has revealed about the origins of biliary atresia – represent progress for a disease badly in need of new therapies. “It is too soon to speculate about what future treatments might look like,” Dr. Shivakumar says. “But having this organoid model accelerates our understanding of biliary atresia. We hope it leads us to improved diagnostics and therapies.”
What’s next: Experts in biliary atresia from diagnosis through long-term care
The Biliary Atresia Program at Children’s Health is one of the highest-volume centers in the nationcaring for patients with biliary atresia. Dr. Bezerra led the international group that developed the MMP-7 blood test to diagnose biliary atresia and Children’s Health is the only clinical lab capable of performing these tests, which speeds diagnoses and improves outcomes. Researchers there are also developing a stool test to improve the diagnostic process.
Learn more about pediatric biliary atresia care at Children’s Health.
