A team of researchers at Stanford Medicine has used genetically engineered human cells to create a model for liver fibrosis, a condition associated with liver damage, scarring and even liver failure.
The new model stems from a previous method that the team developed in 2017 to coax adult stem cells, which can develop into different types of cells, to form the many categories of cells that are found in liver. Together, these cells form an organoid, which is a laboratory model that shows how the cells within an organ interact with each other.
In the researchers' latest work, the cells were engineered to harbor a genetic mutation associated with causing a disease (autosomal recessive polycystic kidney disease) that can lead to liver fibrosis. In studying this disease model, the team, led by Gary Peltz MD, PhD a professor of anesthesiology, perioperative and pain medicine, found that the molecular mechanisms underlying fibrosis weren't exclusive to the genetic disease. In fact, the mechanisms resembled those underlying the more prevalent causes of liver fibrosis, such as chronic alcohol use, viral infections and cancer.
I spoke with Peltz about his team's development of the organoid model, what it's showed so far and how he hopes it will inform treatments for liver fibrosis. This conversation has been lightly condensed and edited for clarity.
How do you traditionally study liver disease? Why is there a need for a new approach?
There are two general methods: You can examine tissues from an animal model or human patients. Examining human tissue provides an investigator with very limited options. The tissue is extremely hard to get and you end up with late-stage tissue that does not provide information about how the disease developed. You just see the end result of the disease process.
The animal models are limited because mice do not develop extensive liver fibrosis, which is the key thing that you're looking for when studying this disease. Moreover, there are significant differences between human and rodent physiology. So, all of these factors limit the utility of animal models for this disease.
Therefore, we wanted to determine whether we could use the system for producing human liver organoids that Yuan Guan, PhD, an instructor at Stanford University School of Medicine, developed in 2017 to probe the mechanism underlying liver fibrosis. And, somewhat surprisingly, we found that introducing this specific genetic mutation caused the key features of autosomal recessive polycystic kidney disease to appear.
What did you find in your study using the organoid?
Most commonly, liver fibrosis is caused by excessive alcohol use, viral diseases or various cancers. Here, we're looking at a rare genetic mutation that produces the same condition. We were surprised to find that when you examine the mechanism generating the fibrosis, we could see striking similarities between what was going on in the organoids that model this genetic disease and what happens in other types of liver fibrosis.
In the genetic and other forms of liver fibrosis, the same type of cell was present and it was in an activated state. Basically, in these different diseases -- irrespective of whether they stem from a genetic, environmental (i.e., alcohol or other toxin) or cancer -- activate the same type of cell that then produces the fibrosis.
It looks like there are some similarities between the different types of liver fibrosis, which makes it an even more interesting than we thought when we started this project.
Where do you go from here?
We want to model additional human genetic diseases where we introduce disease-causing mutations into our model system, and then we will see what happens. We're also introducing various indicators of fibrosis into our model system so we can better analyze the mechanisms that lead to fibrosis.
We want to figure out when the activated cells that cause fibrosis first appear and how extensive they are in the organ. And, most importantly, we will use our model to test therapeutic agents in order to create novel therapies for liver fibrosis.
Photo by natali_mis