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Distinct roles of ecto-nucleoside triphosphate diphosphohydrolase-2 (NTPDase2) in liver regeneration and fibrosis

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Abstract

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.

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Funding

LF received a research fellowship from the Deutsche Forschungsgemeinschaft (DFG; FE1434/1-1), ZGJ was granted a clinical research award from ACG and a clinical translational research award from AASLD, JS received a “Chercheur National” scholarship award from the Fonds de recherche du Québec-Santé (FRQS). This work was also, in part, supported by the National Institutes of Health grants to SCR (NIH; P01HL107152, R21CA164970) and Canadian Institute of Health Research to JS (CIHR; MOP-102472).

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Authors and Affiliations

  1. Department of Surgery, Charité Universitätsmedizin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, 13353, Berlin, Germany

    Linda Feldbrügge & Moritz Schmelzle

  2. Division of Gastroenterology and Hepatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02115, USA

    Linda Feldbrügge, Z. Gordon Jiang, Eva Csizmadia, Shuji Mitsuhashi, Stephanie Tran, Sonja Rothweiler, Kahini A. Vaid, Yury V. Popov & Simon C. Robson

  3. Department of Pathology, University of Arkansas for Medical Sciences, Little Rock, AR, 72205, USA

    Eric U. Yee

  4. Département de Microbiologie-Infectiologie et d’Immunologie, Faculté de Médecine, Université Laval, QC, Québec, G1V 0A6, Canada

    Jean Sévigny

  5. Centre de Recherche du CHU de Québec, Université Laval, QC, Québec, G1V 4G2, Canada

    Jean Sévigny

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  1. Linda Feldbrügge
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Correspondence to Linda Feldbrügge or Simon C. Robson.

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Conflicts of interest

Linda Feldbrügge declares that she has no conflict of interest.

Z. Gordon Jiang declares that he has no conflict of interest.

Eva Csizmadia declares that she has no conflict of interest.

Shuji Mitsuhashi declares that he has no conflict of interest.

Stephanie Tran declares that she has no conflict of interest.

Eric U. Yee declares that he has no conflict of interest.

Sonja Rothweiler declares that she has no conflict of interest.

Kahini A. Vaid declares that she has no conflict of interest.

Jean Sévigny declares that he has no conflict of interest.

Moritz Schmelzle declares that he has no conflict of interest.

Yury V. Popov declares that he has no conflict of interest.

Simon C. Robson declares that he has no conflict of interest.

Ethical approval

The animal experiment protocol was reviewed and approved by the Institutional Animal Care and Use Committee (IACUC) of Beth Israel Deaconess Medical Center.

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Feldbrügge, L., Jiang, Z.G., Csizmadia, E. et al. Distinct roles of ecto-nucleoside triphosphate diphosphohydrolase-2 (NTPDase2) in liver regeneration and fibrosis. Purinergic Signalling 14, 37–46 (2018). https://doi.org/10.1007/s11302-017-9590-3

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