| First Author | Nishimichi N | Year | 2021 |
| Journal | J Pathol | Volume | 253 |
| Issue | 4 | Pages | 366-373 |
| PubMed ID | 33433924 | Mgi Jnum | J:305165 |
| Mgi Id | MGI:6514937 | Doi | 10.1002/path.5618 |
| Citation | Nishimichi N, et al. (2021) Induced hepatic stellate cell integrin, alpha8beta1, enhances cellular contractility and TGFbeta activity in liver fibrosis. J Pathol 253(4):366-373 |
| abstractText | 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 alpha-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 alpha8 subunit. An anti-alpha8 neutralizing mAb was evaluated in three different murine fibrosis models: for cytotoxic (CCl4 treatment), non-alcoholic steatohepatitis-associated and cholestatic fibrosis. In all models, pathology and fibrosis markers (hydroxyproline and alpha-smooth muscle actin) were improved following the mAb injection. We also CCl4 -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 alpha8 suppressed and enhanced myofibroblast differentiation, respectively, and HSC/fibroblast alpha8 activated latent TGFbeta. Finally, integrin alpha8beta1 potentially fulfils the growing need for anti-fibrotic drugs and is an integrin not to be ignored. (c) 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland. |
