In the United States today, approximately one in ten people suffers from liver disease and one in 2,500 children are born with the condition. Liver disease can arise from a number of causes, including genetics, diet, and complications from other diseases and can lead to liver failure, cancer, or death. Liver transplants offer some hope and relief. However, waitlists are long, and many patients succumb before receiving an organ is available.
For many years scientists have marveled both at the liver’s complexity – it performs hundreds of life-sustaining functions – and at its tantalizing capacity for regeneration. In mammals, the liver is the only internal organ with the ability to regrow when damaged or dissected. Naturally, generations of researchers keen on developing more effective treatments for liver disease have sought ways to regenerate liver tissue.
Before regeneration becomes a possibility in the clinic, there are fundamental questions to answer in the lab. Kelly Stevens, PhD, an Assistant Professor of Bioengineering and Lab Medicine and Pathology is a faculty member in the Institute for Stem Cell and Regenerative Medicine (ISCRM). Her lab is harnessing advances in biology and engineering to better understand how the liver works and how to fix it when it doesn’t.
One known factor that inhibits regeneration is scarring – a common result of liver disease. What is less understood, says Stevens, are the forces that underly the relationship between scarring and regeneration. That is the question at the center of the research supported by a recently announced $1 million grant from the W.M. Keck Foundation.
Based in Los Angeles, the W. M. Keck Foundation was established in 1954 by the late W. M. Keck, founder of the Superior Oil Company. The Foundation’s grant making is focused primarily on pioneering efforts in the areas of medical research and science and engineering. The Foundation also supports undergraduate education and maintains a Southern California Grant Program that provides support for the Los Angeles community, with a special emphasis on children and youth.
The grant from the Keck Foundation will fund a three-year effort to shed light on the role of mechanical factors in liver regeneration. Specifically, Stevens and her team will be using a method called Highly Parallel Tissue Grafting to explore the effect of hundreds of customized mechanical microenvironments on human liver regeneration in mice. There are good reasons to use mice. First, previous research has shown that human liver cells are compatible with mouse livers. Second, animal models are more complex than disease-in-a-dish approaches.
“Biologists have tended to focus on the way in which biochemical factors and genes contribute to liver regeneration, mainly because the tools to do this were available and improving,” says Stevens. “The role of mechanical forces in liver regeneration have received much less attention. This is important because when livers become cirrhotic and stiffen, regeneration fails, even though these conditions often progress to cancer, suggesting stiffer environments stimulate proliferation in some conditions.”
It is this paradox that Stevens plans to study with the new grant.
Stevens and her collaborators recently established a powerful new way to model liver regeneration. In this system, artificial liver seeds containing multiple combinations of cell types from human livers are implanted into mice with liver injuries. (Some of these cells will be derived from patients with liver disease.) These seeds, which are produced using 3D printing technology, can also be customized to expressed different degrees of stiffness – one of the key mechanical factors that the researchers hope to understand in more detail.
According to Stevens, the innovation at the heart of the project is the use of high-throughput screening, paired with 3D bioprinting, in the context of a living animal. “By engrafting designer human liver tissue into mice, we can study how different cell populations and different measures of stiffness impact the growth of hepatocytes in various disease states,” explains Stevens. “And, with our high-throughput technology, we can run hundreds of parallel experiments to see how the full range of mechanical microenvironments affects liver regeneration.”
While the research will be limited to the lab for now, Stevens envisions real-world benefits for patients. “Imagine someone with liver cancer. Sometimes, a doctor will be able to cut away the diseased tissue, leaving the healthy tissue to regenerate. But, if too much tissue is removed, the remaining liver won’t regenerate. We believe if we can decipher how mechanical factors affect regeneration, we can learn to control those factors in a therapeutic sense. In other words, to give the patients a regenerative boost.”
Stevens adds that what her team learns will likely have implications for the treatment of other diseases, including heart disease, brain diseases, and neuromuscular diseases. “These are the exciting possibilities that we can only really pursue with a grant like this,” says Stevens. “Thanks to the Keck Foundation, we have the opportunities to ask big, bold questions and use all the tools at our disposal to answer them. The payoff for science and more importantly, for human health, could be profound.”