Advances in stem cell research have made it possible to convert patients’ skin cells into heart cells, kidney cells, liver cells and more in the lab dish, giving researchers hope that one day such cells could replace organ transplantation for patients with organ failure. But successfully grafting these cells into patients’ failing organs remains a major clinical challenge.

Now a team of researchers led by UC San Francisco scientists has demonstrated in mice that it is possible to generate healthy new liver cells within the organ itself, making engraftment unnecessary. What’s more, they did it by converting the very cells that drive liver disease, thereby reducing liver damage and improving liver function at the same time. The technique takes advantage of a viral gene delivery technology that has gone through early validation in patients for liver-directed gene therapies, suggesting it could be readily translated into a therapy for patients with liver disease, said Holger Willenbring, MD, PhD, a professor of surgery at UCSF and senior author of the new study, published in the journal Cell Stem Cell.

“Part of why this works is that the liver is a naturally regenerative organ, so it can deal with new cells very well. What we see is that the converted cells are not only functionally integrated in the liver tissue, but also divide and expand, leading to patches of new liver tissue,” said Willenbring, who is also associate director of the Liver Center at UCSF and a member of the Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research.

The new approach specifically targets liver fibrosis, the progressive scarring of the liver that is a primary driver of liver disease. Fibrosis develops when liver cells called hepatocytes can’t regenerate fast enough to keep up with damage caused by toxins such as alcohol or diseases such as hepatitis B, hepatitis C or fatty liver disease. Cells called myofibroblasts fill in gaps left by dying hepatocytes with scar-like fibrotic tissue. It’s a bit like patching a flat tire: at first the patches help maintain the liver’s structural integrity, but eventually a liver that is more patches than functional tissue starts to fail.

Fibrotic liver disease has a slow fuse, but leads to catastrophic failure: someone who contracts hepatitis C at age 25 may feel just fine for decades, then suddenly at age 50 start experiencing fatigue, nausea, bruising, and jaundice that indicate the onset of end-stage liver disease. The reason is that the liver can adapt as long as at least 20 percent of it is functional, but once it dips below that critical threshold, patients are often dead within two years.

The team showed in mice with liver disease that viruses packed with the cell fate-changing cocktail indeed infected myofibroblasts and converted them into functional hepatocytes. The number of new cells was relatively small – less than one percent of all hepatocytes in the treated mice – but this was sufficient to reduce fibrosis and improve liver function. The viral approach was also effective in converting human myofibroblasts in a dish into working hepatocytes, but more work is certainly needed to prepare this approach for use in human patients, the researchers say. In particular, the lab is working to package the treatment into a single virus, reducing potential side effects and streamlining clinical development. The team is also working to make the viruses more specific to myofibroblasts – in the current paper muscle cells and some cells of the immune system were also infected, though without converting them into liver cells or obviously impacting their function.