Research Projects
Dr. Nyberg leads several ongoing research projects in the Artificial Liver and Liver Transplantation Lab, including efforts to develop an artificial liver and to advance liver regeneration. Read more about our work.
Human liver cell expansion
Hepatitis, cirrhosis, liver cancer, including hepatocellular carcinoma, and other liver diseases affect millions of people around the world. Research on liver disease lags behind other well-studied, prominent diseases because of a lack of appropriate research models.
Our lab is working to overcome this research obstacle. To address the need for a large animal model of hepatocellular carcinoma arising spontaneously within a background of regenerative nodules and cirrhosis, Dr. Nyberg led the development of the first porcine model of hereditary tyrosinemia type 1 (HT1).
Hereditary tyrosinemia type 1 is a liver disease caused by a deficiency in the enzyme fumarylacetoacetate hydrolase (FAH). This disease results in hepatic failure, cirrhosis and liver cancer early in childhood.
The FAH-deficient porcine model was created by targeting and disrupting the porcine FAH gene. The model is phenotypically normal but has decreased FAH transcriptional and enzymatic activity compared with wild-type animals. Our lab is working to use the new model for gene and cell therapy research, especially for studies related to hepatocyte and bone marrow transplantation.
We also envision the HT1 model as an in vivo incubator to grow liver cells, called hepatocytes, from humans, something previously done using FAH mutant mice. The hepatocytes generated in the mice can fully function as adult primary hepatocytes able to perform all the necessary functions required in a human liver. Replicating this success in the larger porcine model is highly desirable since large numbers of human cells are needed for extracorporeal liver assist devices, such as the bioartificial liver. The HT1 model also may be used to grow patient-specific hepatocytes for cell transplantation, avoiding the need for immunosuppression after transplantation.
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Bioartificial livers
Our lab has developed a novel device called the Spheroid Reservoir Bioartificial Liver (SRBAL). This device is being evaluated in a preclinical model of liver failure. The Spheroid Reservoir Bioartificial Liver can act as a potential bridge to liver transplantation. Or it may provide temporary support until spontaneous recovery of the liver. Our ultimate goal is to use this artificial liver device to treat people experiencing liver failure, such as liver failure after a drug overdose.
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Bioengineered replacement livers
In collaboration with industry partner Miromatrix Medical Inc., our lab is developing a protocol for producing transplantable human livers from decellularized pig liver models.
This process involves removing all the liver cells from the model using a continuous perfusion technique. This results in a decellularized bio-scaffold with the original architecture, mechanical properties and a vascular network of a normal liver. The bio-scaffold is recellularized with cell types necessary to restore normal function and blood flow. Our goal is to create a bioengineered replacement liver enabling a large animal model to recover in the absence of native function and survive three months with a normal lifestyle. This milestone is required before considering clinical application and U.S. Food and Drug Administration approval.
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Liver regeneration
Our lab is working to establish new therapies to replace liver transplantation. One alternative is the extracorporeal bioartificial liver device, which has shown a survival benefit and neuroprotective effect in three preclinical large animal models.
Despite these advances, a pharmacological approach to induce liver regeneration would be less invasive and logistically superior to extracorporeal therapy. Indeed, strategies for producing druggable biological targets to stimulate liver regeneration are of therapeutic value and could offer survival benefit. Striving for this goal, RNA interference (RNAi) screening of human tumor cell lines led to the successful identification of the gene mitogen-activated protein kinase kinase 4 (MKK4), whose inhibition leads to a robust elevation in the regenerative capacity of cultured hepatocytes.
To confirm these results in a large animal model, the pig was selected because its liver resembles the human liver in size and function. In addition, the pig hepatectomy model develops signs similar to people with acute liver failure. The model also enables measurement of clinically relevant functional parameters and monitoring of liver size and regeneration using imaging modalities.
Dr. Nyberg's team reported the first randomized preclinical study of LN3348, a novel hepato-regenerative MKK4 inhibitor drug, in a porcine model of post-hepatectomy acute liver failure. Regeneration of the remnant liver was quantified by computerized tomography volumetrics and Ki-67 immunohistochemistry staining. Dr. Nyberg's lab team also observed that LN3348 promoted liver regeneration and improved survival in the porcine hepatectomy model. Clinical testing of this drug is underway. Our lab is continuing to study this new drug and related drugs in other large animal models of liver disease.
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