How the Pathological Microenvironment Affects the Behavior of Mesenchymal Stem Cells in the Idiopathic Pulmonary Fibrosis.

Martina Bonifazi,Monica Mattioli-Belmonte,Majed Refai,Federico Mei,Mariangela Di Vincenzo,Michele Salati,Stefano Gasparini,Lina Zuccatosta,Monia Orciani,Miriam Caffarini

doi:10.3390/ijms21218140

Abstract

Idiopathic pulmonary fibrosis (IPF) is a chronic disease characterized by fibroblasts activation, ECM accumulation, and diffused alveolar inflammation. The role of inflammation in IPF is still controversial and its involvement may follow nontraditional mechanisms. It is seen that a pathological microenvironment may affect cells, in particular mesenchymal stem cells (MSCs) that may be able to sustain the inflamed microenvironment and influence the surrounding cells. Here MSCs have been isolated from fibrotic (IPF-MSCs) and control (C-MSCs) lung tissue; first cells were characterized and compared by the expression of molecules related to ECM, inflammation, and other interdependent pathways such as hypoxia and oxidative stress. Subsequently, MSCs were co-cultured between them and with NHLF to test the effects of the cellular crosstalk. Results showed that pathological microenvironment modified the features of MSCs: IPF-MSCs, compared to C-MSCs, express higher level of molecules related to ECM, inflammation, oxidative stress, and hypoxia; notably, when co-cultured with C-MSCs and NHLF, IPF-MSCs are able to induce a pathological phenotype on the surrounding cell types. In conclusion, in IPF the pathological microenvironment affects MSCs that in turn can modulate the behavior of other cell types favoring the progression of IPF.

Highlights

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and fatal interstitial lung disease (ILD) [1], characterized by an increase of fibroblast proliferation, an excessive extracellular matrix (ECM) deposition [2], and distortion of lung architecture, eventually leading to respiratory failure [3]
Even if many clinical observations [8] suggest the dominant role of fibroblast dysfunction in IPF as opposed to an inflammatory process, inflammation remains a critical factor in IPF through non-traditional mechanisms
Lung tissues from three patients affected by IPF and from three patients undergoing lobectomy for adenocarcinoma were used to establish cell cultures

Summary

Introduction

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and fatal interstitial lung disease (ILD) [1], characterized by an increase of fibroblast proliferation, an excessive extracellular matrix (ECM) deposition [2], and distortion of lung architecture, eventually leading to respiratory failure [3]. In recent years several studies have agreed that IPF does not appear to be the direct result of immune cell dysfunction but rather that immune and inflammatory cells may play a role in fibroproliferation [6]. Observations from clinical studies and experimental models have shown that the stimuli affecting the pulmonary epithelial cells (AEC type II) lead to the activation of fibroblasts in myofibroblast and the accumulation of ECM that can occur without a primary immunopathogenic component [7]. Even if many clinical observations [8] suggest the dominant role of fibroblast dysfunction in IPF as opposed to an inflammatory process, inflammation remains a critical factor in IPF through non-traditional mechanisms

Objectives

Methods

Results