Stem Cells and Liver Regeneration

The liver has an amazing regenerative capacity, which can especially be observed in response to toxic injury and infection. However, in patients with certain hepatic conditions such as cirrhosis, steatosis, and conditions due to age—where liver matrix and cells are compromised—liver regeneration is impaired. In these conditions, where the architecture of the organ is altered, it is still unclear which cellular and molecular pathways prevent regeneration. However, fortunately, in these cases where endogenous regeneration is not possible, new alternatives are being investigated.

Cell therapy for repair of cirrhotic and steatotic livers is a new paradigm being evaluated worldwide. The most prevalent cells being used are self-derived bone marrow–derived mesenchymal stem cells (i.e., bone marrow stromal cells), although umbilical cord blood cell studies are also occurring. As the development of new stem cell sources continues to rapidly expand, it is expected that new liver cell sources will emerge.

Beyond cell therapy are surgical options for repair and regeneration. Full-liver transplant is a last-resort treatment measure, and orthotopic transplantation is the definitive treatment for end-stage organ failure. Criteria for a liver transplant include severe liver damage from alcoholism, chronic hepatitis, and cancer. In 2010, 101,000 people had hospital discharges with chronic liver disease and cirrhosis as the first-listed diagnosis. In the same year 31,903 people died from the same diagnostic causes.

In part because the need is so great and because liver is a regenerative organ, more recently, partial livers (from live donors) have been used for surgical transplantation. This is advantageous not only because it increases the number of donors, but because in recipients improvements in liver function and size occur rapidly. Although partial transplants and cell therapy are promising, they still have not met the need for organ transplant. Since 2009 the number of donors has been stable, despite the increasing need for organs ( Table 104-1 ). As of March 2014 there were 15,275 adults and 484 children on the liver transplant waiting list in the United States ( Table 104-2 ).

Over the past decade the liver transplant life expectancy increased dramatically, primarily because of advancements in technology and experience of the transplant teams. There were 7030 donors in 2013, and 6455 liver transplants were performed with a good survival rate. However, the overall shortage of available donor livers leads to long waiting times, ultimately leading to death before transplantation. There is no doubt the shortage of organs for transplantation remains a significant unmet need.

Not only is liver tissue engineering being developed as a means of increasing the number of donor organs, it is a needed option to reduce the cost of bringing drugs to market. Even though in vitro models have facilitated more efficient drug screening, leading to accelerated preclinical studies in the drug development process, there is still a need for tissue-engineered liver models to recapitulate the in vivo microenvironment. Liver tissue engineering devices are being developed with applications that range from creation and use of extracorporeal biological devices that could potentially bridge patients in liver failure to transplantation, to improving drug-screening platforms for expediting drug development, studying liver organogenesis and liver disease, and finally to restoring lost liver function in vivo through cell, extrahepatic liver organoid, or whole-liver transplantation. This chapter describes new cell therapy and tissue-engineering options being developed for liver repair and regeneration.