Stem Cells in Hepatic Regeneration After Injury

Background: Despite overall cellular quiescence during homeostasis, the liver is one of the few solid organs that maintains near-complete regenerative capacity. In contradistinction to continuously renewing organ systems like the gut, skin, and hematopoietic systems that rely on a well-ordered stem cell hierarchy, in the liver, the fully mature hepatocyte is primarily responsible for maintaining the hepatic parenchyma and its restoration after acute injury. The Problem: A common feature to nearly all forms (congenital-metabolic, acquired-infectious, toxic, and neoplastic) of liver disease is chronic hepatocellular injury that results in an eventual deficit in hepatic regenerative capacity along with increasing inflammation and fibrosis. Currently, the only successful treatment for end-stage liver disease is whole-organ transplantation. Given the severe shortage of suitable organs for transplantation, viable alternatives to liver transplantation are critically needed. Cell-based therapies are promising yet suffer from the lack of a sufficient cell source. Basic/Clinical Science Advances: Recent advances in our basic understanding of hepatic developmental and regenerative biology may lead to novel sources of competent cells for hepatic cell therapy to supplant current whole-organ replacement strategies. Numerous sources, including endogenous facultative hepatic progenitor cells and possible exogenous fetal and embryonic sources of liver stem and progenitor cells, are being enthusiastically pursued. Clinical Care Relevance: To date, a limited number of successful mature hepatocyte transplantation therapies have been achieved for a select number of metabolic diseases. This experience has provided the necessary proof of principle on which to base future hepatocellular therapeutic strategies. Conclusion: In addition to the possibility of utilizing hepatic cells for cellular therapies, the knowledge gained in the study of hepatic regeneration may also lead to novel strategies to prevent hepatocellular exhaustion and thereby ameliorate progressive hepatocellular injury, thus lessening or obviating replacement therapies.