Truncated Milk Fat Globule-EGF-like Factor 8 Ameliorates Liver Fibrosis via Inhibition of Integrin-TGFβ Receptor Interaction

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

doi:10.3390/biomedicines9111529

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 conclusion, this modified MFG-E8 provides a promising new therapeutic strategy for treating fibrotic diseases.

Highlights

IntroductionPublisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations
It is well known that Milk fat globule-epidermal growth factors (EGF) factor 8 (MFG-E8) regulates inflammatory responses by RGD motif binding to immune cells and engulfing phosphatidylserine (PS)-expressing apoptotic cells, it is unclear how MFG-E8 is responsible for the anti-fibrotic effect [18,19]
A recent report showed that the glycosylation-bearing C2 domain of MFG-E8 plays a key role in recognizing PS in apoptotic cells [20]

Summary

Introduction

Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Milk fat globule-EGF factor 8 (MFG-E8), known as lactadherin, is a 46 kDa soluble glycoprotein that plays various roles in physiological and pathological processes, such as facilitating angiogenesis [1], clearing apoptotic cells [2,3], and modulating inflammation [4]. We previously identified a protective role of MFG-E8 in a liver fibrosis model by demonstrating the anti-fibrotic effect of MFG-E8 secreted from mesenchymal stem cells (MSCs) [5]. It has been reported that MFG-E8 resolves fibrosis by direct binding to collagen and facilitates collagen uptake by macrophages in a bleomycin-induced animal model of idiopathic pulmonary fibrosis [6,7]

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