The beneficial paracrine roles of mesenchymal stem cells (MSCs) in tissue repair have potential in therapeutic strategies against various diseases. However, the key therapeutic factors secreted from MSCs and their exact molecular mechanisms of action remain unclear. In this study, the cell-free secretome of umbilical cord-derived MSCs showed significant anti-fibrotic activity in the mouse models of liver fibrosis. The involved action mechanism was the regulation of hepatic stellate cell activation by direct inhibition of the TGF/Smad-signaling. Antagonizing the milk fat globule-EGF factor 8 (MFGE8) activity blocked the anti-fibrotic effects of the MSC secretome in vitro and in vivo. Moreover, MFGE8 was secreted by MSCs from the umbilical cord as well as other tissues, including teeth and bone marrow. Administration of recombinant MFGE8 protein alone had a significant anti-fibrotic effect in two different models of liver fibrosis. Additionally, MFGE8 downregulated TGF type I receptor expression by binding to v3 integrin on HSCs. These findings revealed the potential role of MFGE8 in modulating TGF-signaling. Thus, MFGE8 could serve as a novel therapeutic agent for liver fibrosis. [BMB Reports 2017; 50(2): 58-59]
Detailed understanding of the pathogenesis and development of effective therapies for pulmonary fibrosis (PF) have been hampered by lack of in vitro human models that recapitulate disease pathophysiology. In this study, we generated alveolar organoids (AOs) derived from human pluripotent stem cells (hPSCs) for use as an PF model and for drug efficacy evaluation. Stepwise direct differentiation of hPSCs into alveolar epithelial cells by mimicking developmental cues in a temporally controlled manner was used to generate multicellular AOs. Derived AOs contained the expected spectrum of differentiated cells, including alveolar progenitors, type 1 and 2 alveolar epithelial cells and mesenchymal cells. Treatment with transforming growth factor (TGF-β1) induced fibrotic changes in AOs, offering a PF model for therapeutic evaluation of a structurally truncated form (NP-011) of milk fat globule-EGF factor 8 (MFG-E8) protein. The significant fibrogenic responses and collagen accumulation that were induced by treatment with TGF-β1 in these AOs were effectively ameliorated by treatment with NP-011 via suppression of extracellular signal-regulated kinase (ERK) signaling. Furthermore, administration of NP-011 reversed bleomycin-induced lung fibrosis in mice also via ERK signaling suppression and collagen reduction. This anti-fibrotic effect mirrored that following Pirfenidone and Nintedanib administration. Furthermore, NP-011 interacted with macrophages, which accelerated the collagen uptake for eliminating accumulated collagen in fibrotic lung tissues. This study provides a robust in vitro human organoid system for modeling PF and assessing anti-fibrotic mechanisms of potential drugs and suggests that modified MGF-E8 protein has therapeutic potential for treating PF.
Milk fat globule-EGF factor 8 (MFG-E8) is an anti-inflammatory glycoprotein that mediates a wide spectrum of pathophysiological processes. MFG-E8 has been studied as a key regulator of cancer cell invasion, migration, and proliferation in different tissues and organs. However, potential roles of MFG-E8 in the growth and progression of liver cancer have not been investigated to date. Here, we analyzed 33 human hepatocellular carcinoma (HCC) samples and found that levels of MFG-E8 expression were significantly higher in HCC cells than in normal liver tissues. In addition, our in vitro gain-of-function study in three different HCC cell lines revealed that overexpression of MFG-E8 promoted the proliferation and migration of HCC cells, as determined by RT-qPCR, MTT assays, and wound healing analyses. Conversely, an MFG-E8 loss-of function study showed that proliferation capacity was significantly reduced by MFG-E8 knockdown in HCC cells. Additionally, MFG-E8 activity-neutralizing antibodies profoundly inhibited both migration and proliferation of HCC cells, attenuating their tumorigenic properties. These reductions in migration and proliferation were rescued by treatment of HCC cells with recombinant MFG-E8 protein. Furthermore, an in vivo HCC xenograft study showed that the number of proliferating HCC cells and tumor volume/weight were all significantly increased by MFG-E8 overexpression, compared to control mice. These results clearly show that MFG-E8 plays an important role in HCC progression and may provide a basis for future mechanistic studies and new strategies for the treatment of liver cancer.Cancers 2020, 12, 403 2 of 16 underlying HCC tumorigenesis and identifying novel therapeutic targets are both of great significance in improving the overall prognosis of patients with HCC.Milk fat globule-EGF factor 8 (MFG-E8) is a glycoprotein initially identified as a component of milk fat globules secreted from mammary epithelial cells [3]. Human MFG-E8 consists of an N-terminal EGF-like domain which contains an integrin-binding RGD motif, and two repeated C-terminal discoidin/F5/8C domains that bind phosphatidylserine [3]. Because phosphatidylserine is exposed on the surfaces of apoptotic cells, MFG-E8 has been studied as an opsonin that mediates clearance of dying cells via integrin-expressing phagocytes [4,5]. MFG-E8 is also expressed in many cell types, including mammary epithelial and myoepithelial cells, dendritic cells, endothelial cells, intestinal cells, and retinal epithelial cells. It has been demonstrated that MFG-E8 regulates cellular proliferation, differentiation, and migration under various pathophysiological conditions, including sepsis and age-related diseases [6,7]. We also showed that MFG-E8 is secreted from human umbilical cord mesenchymal stem cells and strongly inhibits the activation of hepatic stellate cells, reducing liver fibrosis both in vitro and in vivo [8].Recent studies have revealed that MFG-E8 is involved in the progression of a variety of tumors, including breast cancer, ovarian canc...
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