Exploring organ-specific features of fibrogenesis using murine precision-cut tissue slices

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE

卷:1866

Article

Bigaeva, Emilia¹  Gore, Emilia¹  Mutsaers, Henricus A. M.^1,2  Oosterhuis, Dorenda¹  Kim, Yong Ook^3,4  Schuppan, Detlef^3,4,5  Bank, Ruud A.⁶  Boersema, Miriam¹  Olinga, Peter¹ 

[1] Univ Groningen, Dept Pharmaceut Technol & Biopharm, Antonius Deusinglaan 1, NL-9713 AV Groningen, Netherlands

[2] Aarhus Univ, Dept Clin Med, Aarhus, Denmark

[3] Johannes Gutenberg Univ Mainz, Univ Med Ctr, Inst Translat Immunol, Obere Zahlbacherstr 63, D-55131 Mainz, Germany

[4] Johannes Gutenberg Univ Mainz, Univ Med Ctr, Res Ctr Immunotherapy, Obere Zahlbacherstr 63, D-55131 Mainz, Germany

[5] Harvard Med Sch, Beth Israel Deaconess Med Ctr, Div Gastroenterol, 330 Brookline Ave, Boston, MA 02215 USA

[6] Univ Groningen, Univ Med Ctr Groningen, Dept Pathol & Med Biol, Groningen, Netherlands

关键词: Precision-cut tissue slices;    Fibrosis;    TGF beta;    Extracellular matrix;    Collagen;    SMAD2;   

DOI  :  10.1016/j.bbadis.2019.165582

来源: Elsevier

【 摘 要 】

Fibrosis is the hallmark of pathologic tissue remodelling in most chronic diseases. Despite advances in our understanding of the mechanisms of fibrosis, it remains uncured. Fibrogenic processes share conserved core cellular and molecular pathways across organs. In this study, we aimed to elucidate shared and organ-specific features of fibrosis using murine precision-cut tissue slices (PCTS) prepared from small intestine, liver and kidneys. PCTS displayed substantial differences in their baseline gene expression profiles: 70% of the extracellular matrix (ECM)-related genes were differentially expressed across the organs. Culture for 48 h induced significant changes in ECM regulation and triggered the onset of fibrogenesis in all PCTS in organ-specific manner. TGF beta signalling was activated during 48 h culture in all PCTS. However, the degree of its involvement varied: both canonical and non-canonical TGFD pathways were activated in liver and kidney slices, while only canonical, Smad-dependent, cascade was involved in intestinal slices. The treatment with galunisertib blocked the TGF beta RI/SMAD2 signalling in all PCTS, but attenuated culture-induced dysregulation of ECM homeostasis and mitigated the onset of fibrogenesis with organ-specificity. In conclusion, regardless the many common features in pathophysiology of organ fibrosis, PCTS displayed diversity in culture-induced responses and in response to the treatment with TGF beta RI kinase inhibitor galunisertib, even though it targets a core fibrosis pathway. A clear understanding of the common and organ-specific features of fibrosis is the basis for developing novel antifibrotic therapies.

【 授权许可】

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