M2 macrophages promote myofibroblast differentiation of LR-MSCs and are associated with pulmonary fibrogenesis

Jiwei Hou,Xiang Chen,Honghui Cao,Jingyan Shi,Zou Xiang,Zhongyang Lv,Xiaodong Han,Ling Chen

doi:10.1186/s12964-018-0300-8

Abstract

BackgroundIdiopathic pulmonary fibrosis (IPF) is a devastating disease characterized by the histopathological pattern of usual interstitial pneumonia and is associated with a high mortality rate. Recently, lung resident mesenchymal stem cells (LR-MSCs) have been identified as an important contributor to myofibroblast activation in pulmonary fibrosis. Macrophages are also believed to play a critical role in pulmonary fibrosis. However, the underlying connections between LR-MSCs and macrophages in the pathogenesis of pulmonary fibrosis are still elusive.MethodsIn this study, we investigated the interaction between LR-MSCs and macrophages using a bleomycin-induced mouse pulmonary fibrosis model and a coculture system.ResultsHere, we show that blocking pulmonary macrophage infiltration attenuated bleomycin-induced pulmonary fibrosis. In addition, as determined by flow cytometry, we discovered that the recruited macrophages in fibrotic lungs of bleomycin-treated mice were mainly M2 macrophages. In particular, we found that M2, rather than M1 macrophages, promoted myofibroblast differentiation of LR-MSCs. Moreover, we demonstrated that suppression of the Wnt/β-catenin signaling pathway could attenuate myofibroblast differentiation of LR-MSCs induced by M2 macrophages and bleomycin-induced pulmonary fibrosis. Tissue samples from IPF patients confirmed the infiltration of M2 macrophages and activation of Wnt/β-catenin signaling pathway.ConclusionIn summary, this study furthered our understanding of the pulmonary fibrosis pathogenesis and highlighted M2 macrophages as a critical target for treating pulmonary fibrosis.

Highlights

Idiopathic pulmonary fibrosis (IPF) is a devastating disease characterized by the histopathological pattern of usual interstitial pneumonia and is associated with a high mortality rate
The myofibroblast differentiation of lung resident mesenchymal stem cells (LR-MSCs) is closely correlated with pulmonary fibrogenesis Following intratracheal spray of bleomycin, the expression of α-smooth muscle actin (α-SMA) and collagen I was increased (Additional file 1: Figure S1), suggesting the occurrence of fibrosis
Our findings suggest that myofibroblast differentiation of LR-MSCs may be a source of myofibroblast accumulation in pulmonary fibrogenesis

Summary

Introduction

Idiopathic pulmonary fibrosis (IPF) is a devastating disease characterized by the histopathological pattern of usual interstitial pneumonia and is associated with a high mortality rate. Lung resident mesenchymal stem cells (LR-MSCs) have been identified as an important contributor to myofibroblast activation in pulmonary fibrosis. Macrophages are believed to play a critical role in pulmonary fibrosis. The underlying connections between LR-MSCs and macrophages in the pathogenesis of pulmonary fibrosis are still elusive. Idiopathic pulmonary fibrosis (IPF) is one of the most common forms of interstitial lung diseases characterized by the deposition of interstitial collagen and other extracellular matrix, leading to dyspnea, cough, impaired lung function, and death [1,2,3]. Recent evidence suggests that lung resident mesenchymal stem cells (LR-MSCs) are precursors of myofibroblasts and can be induced to differentiate. The differentiation of LR-MSCs is sensitive to the microenvironment to which these cells are exposed [11]

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