More than 600,000 patients in the United States alone suffer from end-stage liver disease, or cirrhosis. The only available cure is liver transplantation, but the shortage of donor livers means only 6,000 patients benefit from this therapy each year in the U.S., and more than 35,000 patients die. 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.
However, successfully grafting these cells into patients’ failing organs remains a major clinical challenge. Now, a study from researchers led by UC San Francisco demonstrates in mice that it is possible to generate healthy new liver cells within the organ itself, making engraftment unnecessary. The team state that they did this by converting the very cells that drive liver disease, thereby reducing liver damage and improving liver function at the same time, suggesting that the technique could be readily translated into a therapy for patients with liver disease. The opensource study is published in the journal Cell Stem Cell.
Earlier studies from the lab identified a cocktail of gene-regulating proteins that can convert other cell types into hepatocytes, however, the lab needed a way to deliver these instructions to myofibroblasts. After several years of work, the team identified a subtype of adeno-associated virus (AAV) that could specifically infect myofibroblasts. The researchers focused on AAV because it has been shown to be safe and effective in early human gene therapy trials, for therapy of the bleeding disorder hemophilia B. Therefore, the group have embarked on a different approach, converting fibrosis-causing myofibroblasts into healthy new hepatocytes within the liver itself. The current study shows in mice with liver disease that viruses packed with the cell fate-changing cocktail indeed infected myofibroblasts and converted them into functional hepatocytes.
The current study shows that the number of new cells was relatively small, less than 1% of all hepatocytes in the treated mice, however, this was sufficient to reduce fibrosis and improve liver function. Results show that the viral approach was also effective in converting human myofibroblasts in a dish into working hepatocytes, with more work needed to prepare this approach for use in human patients. Data findings show that the converted cells are functionally integrated in the liver tissue, dividing and expanding to lead to patches of new liver tissue.
Results show that 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 C or fatty liver disease. Data findings show that cells called myofibroblasts fill in gaps left by dying hepatocytes with scar-like fibrotic tissue. The researchers note that at first the patches help maintain the liver’s structural integrity, with a liver that is more patches than functional tissue eventually starting to fail.
The team surmise that their findings suggest that in the fibrotic liver this approach could produce a more efficient and stable improvement of liver function than cell transplant approaches, adding that once the viral packaging is optimized, such a treatment could be done cheaply at a broad range of medical facilities. For the future, the researchers state that in particular, the group is working to package the treatment into a single virus, reducing potential side effects and streamlining clinical development and working to make the viruses more specific to myofibroblasts.
Source: UC San Francisco