Ecto-
nucleoside triphosphate diphosphohydrolases (E-NTPDases) are cell surface-located transmembrane ecto-
enzymes of the CD39 superfamily which regulate
inflammation and tissue repair by catalyzing the phosphohydrolysis of extracellular
nucleotides and modulating purinergic signaling. In the liver,
NTPDase2 is reportedly expressed on portal fibroblasts, but its functional role in regulating tissue regeneration and
fibrosis is incompletely understood. Here, we studied the role of
NTPDase2 in several models of liver injury using global knockout mice. Liver regeneration and severity of
fibrosis were analyzed at different time points after exposure to
carbon tetrachloride (CCl4) or
3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) or partial
hepatectomy in C57BL/6 wild-type and globally NTPDase2-deficient (Entpd2 null) mice. After chronic CCl4 intoxication, Entpd2 null mice exhibit significantly more severe
liver fibrosis, as assessed by
collagen content and histology. In contrast, deletion of
NTPDase2 does not have a substantial effect on biliary-type
fibrosis in the setting of DDC feeding. In injured livers,
NTPDase2 expression extends from the portal areas to fibrotic septae in pan-lobular (CCl4-induced)
liver fibrosis; the same pattern was observed, albeit to a lesser extent in biliary-type (DDC-induced)
fibrosis. Liver regeneration after partial
hepatectomy is not substantively impaired in global Entpd2 null mice.
NTPDase2 protects from
liver fibrosis resulting from hepatocellular injury induced by CCl4. In contrast, Entpd2 deletion does not significantly impact
fibrosis secondary to DDC injury or liver regeneration after partial
hepatectomy. Our observations highlight mechanisms relating to purinergic signaling in the liver and indicate possible therapeutic avenues and new cellular targets to test in the management of hepatic
fibrosis.