Truncated milk fat globule-EGF-like factor 8 ameliorates liver fibrosis via inhibition of integrin-TGfβ receptor interaction

Geun Ho An, Jaehun Lee, Xiong Jin, Jinwoo Chung, Joon Chul Kim, Jung Hyuck Park, Minkyung Kim, Choongseong Han, Jong Hoon Kim, Dong Hun Woo

Research output: Contribution to journalArticlepeer-review

Abstract

Milk fat globule-EGF factor 8 (MFG-E8) protein is known as an immunomodulator in various diseases, and we previously demonstrated the anti-fibrotic role of MFG-E8 in liver disease. Here, we present a truncated form of MFG-E8 that provides an advanced therapeutic benefit in treating liver fibrosis. The enhanced therapeutic potential of the modified MFG-E8 was demonstrated in various liver fibrosis animal models, and the efficacy was further confirmed in human hepatic stellate cells and a liver spheroid model. In the subsequent analysis, we found that the modified MFG-E8 more efficiently suppressed transforming growth factor β (TGF-β) signaling than the original form of MFG-E8, and it deactivated the proliferation of hepatic stellate cells in the liver disease environment through interfering with the interactions between integrins (αvβ3 & αvβ5) and TGF-βRI. Furthermore, the protein preferentially delivered in the liver after administration, and the safety profiles of the protein were demonstrated in male and female rat models. Therefore, in con-clusion, this modified MFG-E8 provides a promising new therapeutic strategy for treating fibrotic diseases.

Original languageEnglish
Article number1529
JournalBiomedicines
Volume9
Issue number11
DOIs
Publication statusPublished - 2021 Nov

Bibliographical note

Publisher Copyright:
© 2021 by the authors. Licensee MDPI, Basel, Switzerland.

Keywords

  • Integrin
  • Liver disease
  • Liver fibrosis
  • Protein therapy
  • TGF-β

ASJC Scopus subject areas

  • Medicine (miscellaneous)
  • General Biochemistry,Genetics and Molecular Biology

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