Influence of CD44 on cell proliferation and fibrosis in Mdr2-/- mice

Background Chronic cholestatic liver injury is linked to inflammation, the emergence of ductular reactions and fibrosis. While expression of CD44, a cellular adhesion molecule, is associated with liver fibrosis in different animal models, it remains unclear if CD44 has a functional role in the processes culminating in the development of hepatic fibrosis. In this study, we investigated the role of CD44 in chronic cholestatic liver injury in Mdr2-/- mice.

Methods Livers of Mdr2-/- (KO) and Mdr2-/-;Cd44-/- (DKO) mice were analyzed by histopathology and immunohistochemistry at different time points to assess liver damage, fibrosis and proliferation markers.

Results In three-months old DKO mice, proliferation in periportal areas was significantly lower than in age-matched Mdr2-/- controls. These findings correlated with reduced numbers of CK19-positive periportal cells in a higher level of fibrosis at 6 months in DKO mice in comparison to KO controls. Interestingly, CD44-deficient Mdr2-/- mice exhibited lower levels of active, nuclear YAP in periportal cells than controls, therefore indicating that CD44 might control proliferation in periportal cells via YAP.

Conclusions In chronic cholestatic liver injury in Mdr2-/- mice, deficiency for CD44 leads to reduced proliferation in periportal areas and decreased expansion of ductular reactions. These findings correlated with reduced YAP expression within ductular reactions in the absence of CD44 – supporting the role of a CD44-YAP axis in the control of periportal proliferation in cholestatic liver injury and protection against fibrosis development.

Publication History

Article published online:
23 January 2024