Rhamm is required for liver repair after acute injury

The liver has an incredible capacity for repair after injury. This involves, in part, dead tissue removal by macrophages and hepatocyte proliferation.  Rhamm (receptor for hyaluronan (HA)-mediated motility) is required for... [ view full abstract ]

The liver has an incredible capacity for repair after injury. This involves, in part, dead tissue removal by macrophages and hepatocyte proliferation.  Rhamm (receptor for hyaluronan (HA)-mediated motility) is required for cell migration after dermal injury and for cell proliferation.  Here, we tested the hypothesis that Rhamm is an important component of the liver wound healing response. To test this hypothesis, we injured mouse livers using carbon tetrachloride and measured various indices of wound-healing in wild-type and Rhamm-/- mice.  Rhamm was not found in uninjured livers, but hepatic Rhamm mRNA and protein content increased robustly 48h after injury, concomitant with hepatic HA accumulation.  Rhamm transcripts were found in hepatocytes and non-parenchymal cells, but were up to 15-fold more abundant in non-parenchymal cells. In Rhamm-/- mice, mRNAs associated with hepatic macrophage content and activation were reduced, and immunofluorescence indicated that macrophage recruitment into necrotic areas was impaired.  Consistently, necrosis persisted in Rhamm-deficient livers relative to necrosis in wild-type mice.  Hepatocyte proliferation was also suppressed in Rhamm-/- mice.  In further support for a role for Rhamm in liver wound healing, wild-type mice with enhanced Rhamm expression exhibited increased hepatic macrophage recruitment, removal of tissue debris, and hepatocyte proliferation relative to wild-type mice with lower Rhamm levels.  Finally, Rhamm-/- mice exhibited reduced hepatic hyaluronan content and pharmacologic inhibition of HA synthesis was associated with reduced Rhamm levels. Taken together, these data firmly support a critical role for Rhamm in liver repair and this likely requires a link between Rhamm and HA.