Bone marrow derived-mesenchymal stem cells downregulate IL17A dependent IL6/STAT3 signaling pathway in CCl4-induced rat liver fibrosis.

Shimaa Farouk,Fatma A Abu Zahra,Akmal A El-Ghor,Salwa Sabet,Maria Cristina Vinci

doi:10.1371/journal.pone.0206130

Shimaa Farouk, Fatma A Abu Zahra + Show 3 more

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https://doi.org/10.1371/journal.pone.0206130

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Abstract

Therapeutic potential of bone marrow–derived mesenchymal stem cells (BM-MSCs) has been reported in several animal models of liver fibrosis. Interleukin (IL) 17A, IL6 and Stat3 have been described to play crucial roles in chronic liver injury. However, the modulatory effect of MSCs on these markers was controversial in different diseases. BM-MSCs might activate the IL6/STAT3 signaling pathway and promote cell invasion in hepatocellular carcinoma, but the immunomodulatory role of BM-MSCs on IL17A/IL6/STAT3 was not fully elucidated in liver fibrosis. In the present study, we evaluated the capacity of the BM-MSCs in the modulation of cytokines milieu and signal transducers, based on unique inflammatory genes Il17a and Il17f and their receptors Il17rc and their effect on the IL6/STAT3 pathway in CCl4-induced liver fibrosis in rats. A single dose of BM-MSCs was administered to the group with induced liver fibrosis, and the genes and proteins of interest were evaluated along six weeks after treatment. Our results showed a significant downregulation of Il17a, Il17ra, il17f and Il17rc genes. In accordance, BM-MSCs administration declined IL17, IL2 and IL6 serum proteins and downregulated IL17A and IL17RA proteins in liver tissue. Interestingly, BM-MSCs downregulated both Stat3 mRNA expression and p-STAT3, while Stat5a gene was downregulated and p-STAT5 protein was elevated. Also P-SMAD3 and TGFβR2 proteins were downregulated in response to BM-MSCs treatment. Collectively, we suggest that BM-MSCs might play an immunomodulatory role in the treatment of liver fibrosis through downregulation of IL17A affecting IL6/STAT3 signaling pathway.

Highlights

Liver fibrosis represents the final common pathway of virtually all chronic liver diseases including viral hepatitis, alcohol or drug abuse and metabolic diseases [1], and represents the first step toward a number of often mortal complications of liver disease
Recent studies illustrated the crucial role that interleukin 17A (IL17A) plays in the development and progression of hepatic fibrosis [14], along with the anti-fibrotic activity of bone marrow-derived Mesenchymal stem cells (MSCs) (BM-MSCs) [12, 43]
We demonstrated a therapeutic potential of BM-MSCs in CCl4-induced rat liver fibrosis through inhibition of IL17A/F isoforms expressed genes and IL17 associated signaling pathway

Summary

Introduction

Liver fibrosis represents the final common pathway of virtually all chronic liver diseases including viral hepatitis, alcohol or drug abuse and metabolic diseases [1], and represents the first step toward a number of often mortal complications of liver disease. Mesenchymal stem cells ameliorate liver fibrosis and modulate cytokines milieu and signal transducers treatment for liver fibrosis, aside from liver transplantation, has not been established yet [2]. Alternative treatments have been considered such as stem cells transplantation as these cells have the ability of self-renewal and differentiation [3]. Mesenchymal stem cells (MSCs) are multipotent adult stem cells that have the ability to differentiate into hepatocyte like cells [4, 5], and have the capacity to secrete a series of cytokines and signaling molecules [6, 7] which can regulate inflammatory responses, stimulate hepatocyte proliferation, and maintain hepatocyte function [8]. Anti-fibrotic activities of MSCs have been reported in fibrotic animal models [11, 12]

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