Rebooting cell programming via precision medicine reverses liver failure in animal model.


A team of researchers from the University of Pittsburgh state that it might be possible to heal cirrhotic liver disease by rebooting the genes that control liver cell function. If validated in human studies, the game-changing strategy, described in an opensource study published in the Journal of Clinical Investigation, could potentially treat patients who are too sick for liver transplantation and, in the future, reduce the need for transplants.

The project grew out of the observation that not everyone who develops cirrhosis, or scarring of the liver, progresses to liver failure and its life threatening complications.

Even with the large amount of scar tissue that comes with cirrhosis, there should still be enough cells left to carry out the normal functions of the liver.  So when the liver fails, it is the liver cells themselves that aren’t working properly. In this study, the team has  demonstrated what has caused the problem, and more importantly, a way to repair it.

In the current study the researchers team developed a rat model of liver disease that mimics the form of human cirrhosis that progresses to organ failure. In previous work, they found that liver cells taken from animals with cirrhosis, but no liver failure, immediately functioned properly when transplanted into another animal. But cells transplanted from animals with both cirrhosis and liver failure did not function normally at first, indicating that both the liver cells and the liver tissue environment were damaged.

The researchers then compared the genes in the liver cells of the two groups of cirrhotic rats and found unusually low activity levels of the genes that control proteins which play a central role in liver cell function, the most important being a factor called HNF4.  In the current study the team showed that restoring production of HNF4 by precision medicine reboots the liver cells to normal function. The team first showed this in lab tests and then in rats with liver failure.

The researchers noted that the animals got better almost immediately. Remarkably, the tests indicated that it wasn’t stem cells, regeneration or growth of new liver cells that caused improvement. Instead, the diseased cells had healed.  It seems that in at least some forms of cirrhosis, chronic injury reprograms the liver cells to shut down HNF4 production, a dysfunction that eventually causes liver failure.

HNF4 precision medicine provided unique insight into the cause of liver failure and has significant potential for human therapy, but the investigators are now looking for other gene targets to develop simpler therapies, such as drugs that block the pathways that mediate failure. The team is now confirming their results with human liver cells.

Source:  The University of Pittsburgh School of Medicine

 

Schematic diagram for the induction of irreversible degenerative liver disease and terminal hepatic failure in rats and changes in HNF4α expression with disease progression.  (A) Schematic diagram of the phenobarbital and CCl4 treatment protocol. Scale bar: 100 µm.  Resetting the transcription factor network reverses terminal chronic hepatic failure.  Fox et al 2015.

Schematic diagram for the induction of irreversible degenerative liver disease and terminal hepatic failure in rats and changes in HNF4α expression with disease progression. (A) Schematic diagram of the phenobarbital and CCl4 treatment protocol. Scale bar: 100 µm. Resetting the transcription factor network reverses terminal chronic hepatic failure. Fox et al 2015.

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