Scientists have developed a functional human hepatic tissue in a mouse host. The human hepatic tissue, in the mice, is composed of human hepatocytes and non-parenchymal cells (NPCs) including human immune, endothelial, and stellate cells.
Because the humanized livers, in living mice, reproduce human liver architecture, perform human-specific processes, and model human pathologies, they will aid scientists find human-specific mechanisms for regulating cholesterol levels and potentially for treating chronic liver diseases.
The findings are published in Cell, in the article, “Humanized mouse liver reveals endothelial control of essential hepatic metabolic functions.”
Chronic liver diseases such as alcoholic and non-alcoholic liver disease, cancer, viral hepatitis, fibrosis, and cancer affect more than 1.5 billion people worldwide. In the United States, an estimated 30 to 40% of the population has been diagnosed with non-alcoholic fatty liver disease (NAFLD) alone. Yet liver disease has been difficult to study in animal models. The livers of mice, for instance, perform different functions than those of humans.
“Inside the liver, multiple human cell types talk in their own language,” said Richard Flavell, PhD, professor of immunobiology at Yale School of Medicine and HHMI investigator. “Mouse and human cells talk in different languages, but we have enabled human liver cells to speak in their own language within living mice.”
For the study, a team of scientists led by Eleanna Kaffe, an associate research scientist in Flavell’s Lab, used progenitor stem cells and mature hepatocytes from a human liver to create a complete human liver in a mouse model. The humanized livers reproduce human liver architecture, perform vital human-specific metabolic/homeostatic processes, and model human pathologies, including fibrosis and NAFLD.
The authors noted that by leveraging species mismatch and lipidomics, they were able to demonstrate that human NPCs control the metabolic functions of human hepatocytes in a paracrine manner.
The researchers also found that essential liver metabolism is controlled by activity in endothelial cells, which line blood vessels that feed the liver. Those endothelial cells, they found, secrete the signaling molecule Wnt which regulates cholesterol transport to hepatocytes for the synthesis of bile acid. The transport of cholesterol to hepatocytes is an important mechanism that reduces excess blood cholesterol levels in humans.
More specifically, the authors wrote that they uncovered “a species-specific interaction whereby WNT2 secreted by sinusoidal endothelial cells controls cholesterol uptake and bile acid conjugation in hepatocytes through receptor FZD5.”
According to the researchers, the humanized liver model can be used immediately by drug companies seeking to assess the safety of experimental drugs designed to treat chronic diseases.
“However, our long-term goal is to find ways to predict, prevent, and treat all liver diseases, which take such a huge toll on individuals,” they noted.