GATA4 loss in the septum transversum mesenchyme promotes liver fibrosis in mice

Authors

  • Irene Delgado,

    1. Centro Andaluz de Biología Molecular y Medicina Regenerativa (CABIMER), Sevilla, Spain
    2. Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Barcelona, Spain
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  • Manuel Carrasco,

    1. Centro Andaluz de Biología Molecular y Medicina Regenerativa (CABIMER), Sevilla, Spain
    2. Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Barcelona, Spain
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  • Elena Cano,

    1. Department of Animal Biology, Faculty of Science, University of Malaga, Málaga, Spain
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  • Rita Carmona,

    1. Department of Animal Biology, Faculty of Science, University of Malaga, Málaga, Spain
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  • Rocío García-Carbonero,

    1. Oncology Unit, Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/Consejo Superior de Investigaciones Científicas/Universidad de Sevilla, Hospital Universitario Virgen del Rocío, Sevilla, Spain
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  • Luis M. Marín-Gómez,

    1. Surgical Department, IBiS, Hospital Universitario Virgen del Rocío/Consejo Superior de Investigaciones Científicas/Universidad de Sevilla, Sevilla, Spain
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  • Bernat Soria,

    1. Centro Andaluz de Biología Molecular y Medicina Regenerativa (CABIMER), Sevilla, Spain
    2. Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Barcelona, Spain
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  • Francisco Martín,

    1. Centro Andaluz de Biología Molecular y Medicina Regenerativa (CABIMER), Sevilla, Spain
    2. Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Barcelona, Spain
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  • David A. Cano,

    1. Endocrinology Unit, IBiS, Hospital Universitario Virgen del Rocío/Consejo Superior de Investigaciones Científicas/Universidad de Sevilla, Sevilla, Spain
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  • Ramón Muñoz-Chápuli,

    1. Department of Animal Biology, Faculty of Science, University of Malaga, Málaga, Spain
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  • Anabel Rojas

    Corresponding author
    1. Centro Andaluz de Biología Molecular y Medicina Regenerativa (CABIMER), Sevilla, Spain
    2. Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Barcelona, Spain
    • Address reprint requests to: Anabel Rojas, Ph.D., Centro Andaluz de Biología Molecular y Medicina Regenerativa, Avenida Americo Vespucio s/n Parque Científico Isla de la Cartuja, 41092 Sevilla, Spain. E-mail: anabel.rojas@cabimer.es; fax: +34 954 461 664.

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  • Potential conflict of interest: Nothing to report.

  • I.D. was supported by a contract from Consejería de Salud, Junta de Andalucía (PI-0008). M.C. is a recipient of a predoctoral fellowship from Spanish Ministry of Education (AP2009-2582). E.C. is a recipient of a MINECO fellowship (BES-2009-014847). This work was supported by grants from ISCIII cofunded by Fondos FEDER, PI11/01125 to A.R., BFU2011-25304 (Ministerio de Economía y Competitividad), P11-CTS-7564 (Junta de Andalucía), and RD12/0019/0022 (TerCel network, ISCIII) to R.M.Ch., the Spanish Ministry of Science and Innovation (SAF2008-02469 and SAF2011-26805) and the Andalusian Regional Ministry of Economy, Science and Innovation (P08-CVI-3727) to D.A.C., and Instituto de Salud Carlos III (cofunded by FEDER: Red TerCel grants RD06/0010/0025 and PI10/00964), Consejería de Innovación Ciencia y Empresa, Junta de Andalucía (grant CTS-6505), the Ministry of Health and Consumer Affairs (Advanced Therapies Program Grant TRA-120), and the European Union: BIOREG SOE3/P1/E750 (cofunded by FEDER) to B.S.

Abstract

The zinc finger transcription factor GATA4 controls specification and differentiation of multiple cell types during embryonic development. In mouse embryonic liver, Gata4 is expressed in the endodermal hepatic bud and in the adjacent mesenchyme of the septum transversum. Previous studies have shown that Gata4 inactivation impairs liver formation. However, whether these defects are caused by loss of Gata4 in the hepatic endoderm or in the septum transversum mesenchyme remains to be determined. In this study, we have investigated the role of mesenchymal GATA4 activity in liver formation. We have conditionally inactivated Gata4 in the septum transversum mesenchyme and its derivatives by using Cre/loxP technology. We have generated a mouse transgenic Cre line, in which expression of Cre recombinase is controlled by a previously identified distal Gata4 enhancer. Conditional inactivation of Gata4 in hepatic mesenchymal cells led to embryonic lethality around mouse embryonic stage 13.5, likely as a consequence of fetal anemia. Gata4 knockout fetal livers exhibited reduced size, advanced fibrosis, accumulation of extracellular matrix components and hepatic stellate cell (HSC) activation. Haploinsufficiency of Gata4 accelerated CCl4-induced liver fibrosis in adult mice. Moreover, Gata4 expression was dramatically reduced in advanced hepatic fibrosis and cirrhosis in humans. Conclusions: Our data demonstrate that mesenchymal GATA4 activity regulates HSC activation and inhibits the liver fibrogenic process. (Hepatology 2014;59:2358–2370)

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