Cell type-specific role of CD44 in liver regeneration

Background: CD44, a cellular adhesion molecule involved in liver regeneration and fibrosis, shows increased expression after liver injury. In cholestatic injury, it localizes around ductular reactions (DR) near the portal triad, while exhibiting a distinct pattern in hepatocytes during liver damage. However, its functional role in liver regeneration across different injury models remains uncertain.

Methods: This study investigated CD44's role in both acute and chronic liver injury using Cd44-/- (KO) mice compared to wildtype C57BL/6J mice in different liver damage models. Acute liver injury of hepatocytes was induced with a choline-deficient, ethionine-supplemented (CDE) diet, while acute bile duct injury was targeted using a DDC diet. Chronic cholestasis was modeled in Mdr2-/;Cd44-/- and Mdr2-/- mice. Liver tissue samples were collected and analyzed for CD44 expression and the proliferation marker KI67.

Results: In CDE diet-induced acute injury, CD44-deficient mice showed significantly lower number of proliferative (KI67+) cells and decreased hepatocyte proliferation (p=0.0175). In chronic cholestatic injury, a significant difference in DR proliferation (p=0.0421) was observed between Mdr2-/-; Cd44-/- and Mdr2-/- mice after 3 months, with no change in hepatocyte proliferation. YAP (yes-associated protein) seems to be upregulated by CD44 in cholestatic injury models (p=0.0131), potentially explaining the increased proliferation in DR. However, in the CDE diet model, targeting hepatocyte damage, Cd44 knockout does not affect YAP expression.

Conclusion: These findings highlight the cell type-specific and possibly injury-dependent role of CD44 in liver regeneration. We further aim to identify differential mechanisms mediating CD44-dependent cell proliferation.

Publication History

Article published online:
20 January 2025