Health breakthrough: Mini human livers grown in labs could bring hope to hundreds of thousands suffering fatal liver disease

The mini-livers grown from human stem cells can mimic many aspects of human non-alcoholic fatty liver disease and its progression

                            Health breakthrough: Mini human livers grown in labs could bring hope to hundreds of thousands suffering fatal liver disease

Researchers have recently grown mini human livers in the laboratory from human stem cells, to mimic how a fatal liver disease develops and advances, and to test treatments. It is common for drugs to fail in clinical trials, despite promising results in animal models. Hence, these mini livers could become an important and reliable tool for studying diseases of the liver and testing drugs at all stages of disease development as well as help solve liver diseases.

Terminal liver failure causes about 30,000 deaths in the US annually, and the only definitive treatment is liver transplantation. But the shortage of donors livers and the high cost of the procedure are limiting factors. "During the past 20 years, liver transplantation has become the definitive treatment for most severe types of liver failure and hepatocellular carcinoma, in both children and adults. In the US, roughly 16,000 individuals are on the liver transplant waiting list. Only 38% of them will receive a transplant due to the organ shortage," says a 2015 study published in PLOS One.

The second cause of liver failure results from progressive damage caused by alcoholic and non-alcoholic fatty liver disease. More than 100 million Americans suffer from non-alcoholic fatty liver disease — a condition involving fat buildup in the liver, which can lead to cirrhosis or even liver failure. This number is rapidly increasing in parallel with worldwide obesity and diabetes epidemics.

Researchers describe the non-alcoholic fatty liver disease as a "multisystem disease that affects the liver and leads to an increased risk of diabetes, as well as cardiovascular and kidney diseases". But how this disease progresses remains unclear. 

This is what makes the lab-grown mini-livers a critical innovation as they emulate many aspects of human non-alcoholic fatty liver disease and its progression to a more severe condition known as non-alcoholic steatohepatitis or NASH. This will enable researchers to study how the disease advances and figure out how to intervene.

The lab-grown mini liver (UPMC)

In a proof-of-concept paper published in Cell Metabolism, a research team at the University of Pittsburgh School of Medicine describe how they transformed genetically engineered human cells into functional, 3D liver tissue. "This is the first time we have genetically engineered entire mini-human livers using induced pluripotent stem cells (iPS), a type of stem cell that can be generated from adult skin or blood cells. That's important not only for understanding what causes the disease and how it progresses but also for testing therapeutics," says the team.

The researchers designed the current study to modify the expression of only one gene — SIRT1, which in normal livers is in charge of regulating fat metabolism and controlling liver inflammation — to understand the non-alcoholic fatty liver disease and its progression.

“Mice aren't humans. We are born with certain mutations and polymorphisms that will predispose us to certain diseases, but you can't study polymorphisms in mice, so making a mini customized human liver is advantageous," says senior author Dr. Alejandro Soto-Gutierrez, associate professor of pathology at Pitt's School of Medicine and faculty member of the McGowan Institute for Regenerative Medicine and the Pittsburgh Liver Research Center.

To further explain their point, the research team says that the drug Resveratrol, which acts on SIRT1 proteins commonly associated with non-alcoholic fatty liver disease, was effective in mouse models, but failed in human clinical trials.

To create the mini livers, the team collected adult skin cells from a healthy person and grew them in the lab. They then genetically modified these cells to turn off the gene called SIRT1. Then, they reprogrammed the cells back to their stem cell state and turned them into liver cells. After that, they seeded the genetically engineered human liver cells into rat livers stripped of their own cells, where they grew into functional 3D mini livers with blood vessels and other structural features of a normal organ. The mini liver measures between five and seven centimeters across. 

A device that sustains the mini-liver (UPMC)

"Once the mini livers were mature, we flipped the genetic switch to suppress the SIRT1 gene, and the bioengineered mini livers started to mimic the metabolic dysfunction observed in tissues from patients with fatty liver disease," state the findings.

But just like the clinical trials, Resveratrol was not effective in the lab-grown livers. "Resveratrol boosts the activity of SIRT1 proteins, not SIRT1 genes. If SIRT1 gene expression is suppressed — like it is in the bioengineered livers, and perhaps also non-alcoholic fatty liver disease patients — there is no protein to act on, so the drug will not work. It's targeting the wrong step. That's an insight that could only come from studying functional human tissue," says Soto-Gutierrez. 

According to the researchers, these mini-livers may be more accurate than mice to ascertain whether a drug will be useful in humans. Future research and experiments will focus on controlling the function of many genes simultaneously, as well as examining how to modify these mini livers to make more accurate replicas of the liver.

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