Stem cell factor and c-kit are involved in hepatic recovery after acetaminophen-induced liver injury in mice

• Published in: American journal of physiology: Gastrointestinal and liver physiology 2008-07, Vol.295 (1), p.G45-G53
• Main Authors: Hu, Bin, Colletti, Lisa M
• Format: Article
• Language: English
• Subjects: Acetaminophen - toxicity; Alanine Transaminase - blood; Analgesics; Animals; Anti-Inflammatory Agents, Non-Steroidal - toxicity; Apoptosis; Aspartate Aminotransferases - blood; Cell Proliferation - drug effects; Chemical and Drug Induced Liver Injury - metabolism; Cytokines; Gene Deletion; Gene Expression Regulation - physiology; Hepatocytes - cytology; Hepatocytes - drug effects; Hepatocytes - metabolism; Hydrogen Peroxide - toxicity; Liver; Liver - drug effects; Liver - enzymology; Liver - pathology; Liver and Biliary Tract; Mice; Mice, Inbred C57BL; Mice, Knockout; Proto-Oncogene Proteins c-kit - genetics; Proto-Oncogene Proteins c-kit - metabolism; Ribonucleic acid; RNA; Rodents; Stem Cell Factor - metabolism; Stem Cell Factor - pharmacology; Stem cells; Time Factors
• ISSN: 0193-1857; 1522-1547
• DOI: 10.1152/ajpgi.00024.2008

Stem cell factor (SCF) and its receptor c-kit are important in hematopoiesis and cellular proliferation. c-kit has also been identified as a cell surface marker for progenitor cells. We have previously shown that there is a large reservoir of hepatic SCF, and this molecule plays a significant role in liver regeneration after 70% hepatectomy. In the current study, we further examined the expression of SCF and c-kit in acetaminophen (APAP)-induced liver injury in C57BL/6J mice or SCF-deficient sl-sld mice and their appropriate wild-type controls. Following APAP-induced liver injury, c-kit mRNA expression increased, with peak levels detected 48 h postinjury. Hepatic SCF mRNA levels after APAP injury were also increased, with peak levels seen 16 h post-APAP. The mortality rate in SCF-deficient mice treated with APAP was significantly higher than that of wild-type mice; furthermore, administration of exogenous SCF significantly reduced the mortality of APAP-treated wild-type mice. Bromodeoxyuridine incorporation experiments showed that SCF significantly increased hepatocyte proliferation at 48 and 72 h in APAP-treated mice. SCF inhibited APAP-induced hepatocyte apoptosis and increased Bcl-2 and Bcl-xL expression, suggesting that this decrease in hepatocyte apoptosis is mediated through Bcl-2 and Bcl-xL. In summary, SCF and c-kit expression was increased after APAP-induced liver injury. Administration of exogenous SCF reduces mortality in APAP-treated mice, increases hepatocyte proliferation, and prevents hepatocyte apoptosis induced by APAP, suggesting that these molecules are important in the liver's recovery from these injuries.