May 07, 2019 02:20 PM EDT
New molecular targets may aid in the treatment of congenital hepatic fibrosis, according to a research group centered at Tokyo Medical and Dental University (TMDU).
A rare genetic disease that causes malformation and fibrosis (scarring) of the liver is congenital hepatic fibrosis (CHF). It happens roughly one out of every 20,000 births, and it can lead to an enlarged liver, impaired blood flow to the intestines (portal hypertension), infection of the bile ducts and liver failure. Patients may need a liver transplant in severe cases to treat the disease.
Researchers have published a new study in the Journal of Hepatology, and they described a new experimental model of CHF which allowed them to uncover molecular players that may contribute to the illness.
The corresponding author of the study, Sei Kakinuma explained that CHF is quite different from more prevalent liver diseases which lead to cirrhosis. As an example, CHF's symptoms are not caused by cellular necrosis as they are in hepatitis. There is an essential genetic component underlying CHF because patients often have mutations in a particular gene, PKHD1, coding fibrocystin. But it is not exactly clear how these mutations contribute to the unusual symptoms of the disease.
The investigators relied on experimental models to study CHF, and these usually involve mice with mutations in PKHD1. Though useful, mouse models often have additional liver pathologies that are rarely seen in patients with CHF. Patient-derived stem cells are problematic, too, because mutations in PKHD1 differ from patient to patient and the effect of different mutations on the disease is poorly understood. To get around these drawbacks, the researchers used the genome editing technology CRISPR/Cas9 which allowed them to engineer their own human stem cells model in CHF.
The first author of the study, Tomoyuki Tsunoda explained that their approach was to take stem cells from healthy subjects and induce a specific mutation in PKHD1. The precision of CRISPR allowed them to make a targeted genetic change that completely abolishes the expression of the protein coded by the gene. Then, they assessed the molecular and pathological behavior of the stem cells, knowing with confidence that they had rendered the PKHD1 gene completely inactive.
The direction of some of the prior studies had not pinpointed molecules whose expression changed as a result of mutated PKHD1. Now, the research team was able to scour the genetic landscape for fundamental molecular changes. They discovered that the expression of two genes, IL-8 and CTGF, was significantly increased as a result of the PKHD1 mutation. Both IL-8 and CTGF appear to play critical roles in the progression of the disease, and importantly, they found their expression at abnormally high levels in the livers of CHF patients.
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