Liver transplantation—the transfer of a whole liver or a portion of one—is the only proven treatment for end-stage liver disease and acute liver failure (ALF). But it’s no panacea. The main problem is that supply can’t keep up with demand: For end-stage liver disease patients on a waiting list for a transplant, the fatality rate can be as high as 20%; and the fatality rate for patients with ALF can exceed 60%. Even those lucky enough to qualify for a donor liver face an uncertain future.
The surgical procedure is complex, not always successful, and extremely expensive. And for the rest of their lives, liver recipients must take immunosuppressant drugs, which prevent the body from rejecting the foreign organ but often cause serious side effects. Simpler, cheaper and more widely available alternatives are urgently needed.
For the past three decades, Sanjeev Gupta, M.D., professor of medicine and of pathology and the Eleazar and Feige Reicher Chair in Translational Medicine at Einstein, has worked to develop cell and molecular therapies that might regenerate the liver and thereby substitute for liver transplants.
In a paper published online on March 8 in The FASEB Journal, Dr. Gupta and colleagues including lead author Preeti Viswanathan, M.D., assistant professor of pediatrics at Einstein, studied whether cell therapy could help in treating ALF due to excessive acetaminophen (Tylenol) ingestion—the leading cause of ALF in children and adults.
Studies of cell therapy for treating ALF include infusing healthy liver cells from donors into the abdominal cavity, which contains the liver. (Putting cells directly into the liver itself can aggravate an injury and make matters worse.) After engrafting (implanting) in the abdominal cavity, the donated cells carry out some of the liver’s missing functions and also send signals to the damaged liver that help it regenerate. Using a mouse model of acetaminophen toxicity, Dr. Gupta’s team identified a cell type capable of replacing signals that are missing in acetaminophen-induced ALF as well as key signaling pathways that must be reactivated for liver regeneration to occur.
The Einstein researchers found that two types of transplanted donor liver cells—hepatocytes and sinusoidal endothelial cells—engrafted successfully in the abdominal cavity of acetaminophen-toxicity mice. However, only hepatocytes, which are the chief functional cells that make up the liver, could rescue these mice by inducing liver regeneration.
Moreover, the donor hepatocytes were found to secrete critical cytokine proteins—GCSF, VEGF, and others—that the damaged livers of recipient mice no longer made in adequate amounts. These cytokines restored two signaling pathways (ATM and JAK/STAT3) needed to advance DNA repair and liver regeneration.
The study showed that donor hepatocytes show promise for treating acetaminophen-induced ALF in people. The findings also suggest that this type of ALF could potentially be treated in new ways including by targeting the ATM and JAK/STAT3 signaling pathways.
Posted on: Wednesday, March 17, 2021