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Induced hepatic stellate cell integrin, α8β1, enhances cellular contractility and TGFβ activity in liver fibrosis
Author(s) -
Nishimichi Norihisa,
Tsujino Kazuyuki,
Kanno Keishi,
Sentani Kazuhiro,
Kobayashi Tsuyoshi,
Chayama Kazuaki,
Sheppard Dean,
Yokosaki Yasuyuki
Publication year - 2021
Publication title -
the journal of pathology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.964
H-Index - 184
eISSN - 1096-9896
pISSN - 0022-3417
DOI - 10.1002/path.5618
Subject(s) - hepatic stellate cell , myofibroblast , fibrosis , integrin , fibroblast , downregulation and upregulation , hepatic fibrosis , cancer research , extracellular matrix , hydroxyproline , pathology , microbiology and biotechnology , chemistry , biology , medicine , immunology , receptor , cell culture , endocrinology , biochemistry , gene , genetics
No effective therapy exists for fatal fibrosis. New therapeutic targets are needed for hepatic fibrosis because the incidence keeps increasing. The activation and differentiation of fibroblasts into myofibroblasts that causes excessive matrix deposition is central to fibrosis. Here, we investigated whether (and which) integrin receptors for matrix proteins activate hepatic stellate cells (HSCs). First, integrin α‐subunits were investigated systematically for their expression over the course of HSC activation and their distribution on fibroblasts and other systemic primary cells. The most upregulated in plate culture‐activated HSCs and specifically expressed across fibroblast linages was the α8 subunit. An anti‐α8 neutralizing mAb was evaluated in three different murine fibrosis models: for cytotoxic (CCl 4 treatment), non‐alcoholic steatohepatitis‐associated and cholestatic fibrosis. In all models, pathology and fibrosis markers (hydroxyproline and α‐smooth muscle actin) were improved following the mAb injection. We also CCl 4 ‐treated mice with inducible Itga8−/− ; these mice were protected from increased hydroxyproline levels. Furthermore, ITGA8 was upregulated in specimens from 90 patients with liver fibrosis, indicating the relevance of our findings to liver fibrosis in people. Mechanistically, inhibition or ligand engagement of HSC α8 suppressed and enhanced myofibroblast differentiation, respectively, and HSC/fibroblast α8 activated latent TGFβ. Finally, integrin α8β1 potentially fulfils the growing need for anti‐fibrotic drugs and is an integrin not to be ignored. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.