Human Mesenchymal Stem Cells Suppress the Stretch–Induced Inflammatory miR-155 and Cytokines in Bronchial Epithelial Cells

Yi-Chun Kuo,Marina Miller,Yi-Shuan Julie Li,Shu Chien,Oscar Kuang-Sheng Lee,Jing Zhou,Yu-Ru Vernon Shih,David Broide,Jin Q Cheng

doi:10.1371/journal.pone.0071342

Abstract

Current research in pulmonary pathology has focused on inflammatory reactions initiated by immunological responses to allergens and irritants. In addition to these biochemical stimuli, physical forces also play an important role in regulating the structure, function, and metabolism of the lung. Hyperstretch of lung tissues can contribute to the inflammatory responses in asthma, but the mechanisms of mechanically induced inflammation in the lung remain unclear. Our results demonstrate that excessive stretch increased the secretion of inflammatory cytokines by human bronchial epithelial cells (hBECs), including IL-8. This increase of IL-8 secretion was due to an elevated microRNA-155 (miR-155) expression, which caused the suppression of Src homology 2 domain–containing inositol 5-phosphatase 1 (SHIP1) production and the subsequent activation of JNK signaling. In vivo studies in our asthmatic mouse model also showed such changes in miR-155, IL-8, and SHIP1 expressions that reflect inflammatory responses. Co-culture with human mesenchymal stem cells (hMSCs) reversed the stretch-induced hBEC inflammatory responses as a result of IL-10 secretion by hMSCs to down-regulate miR-155 expression in hBECs. In summary, we have demonstrated that mechanical stretch modulates the homeostasis of the hBEC secretome involving miR-155 and that hMSCs can be used as a potential therapeutic approach to reverse bronchial epithelial inflammation in asthma.

Highlights

Physical forces, including shear stress and stretching force, influence the structure, function and metabolism of lung cells [1,2,3]
Using a mouse cytokine Multi-Analyte ELISArray Kit (SABiosciences), we demonstrated that mice challenged with ovalbumin (OVA) exhibited significant increases of the pro-inflammatory cytokines interleukin 1A, 1B, 4, 5, 6, 8, 12 and 13, and decreases of the anti-inflammatory cytokine interleukin 10 (IL-10) in their bronchoalveolar lavage (BAL) (Fig. 1A)
We tested the regulation of IL-10 expression and secretion in human mesenchymal stem cells (hMSCs) and human bronchial epithelial cells (hBECs) by hyperstretch

Summary

Introduction

Physical forces, including shear stress and stretching force, influence the structure, function and metabolism of lung cells [1,2,3]. Cells in the respiratory airway are constantly exposed to mechanical stretches due to cyclic expansions and deflations of the lung. The lungs in asthma patients with increased respiration rates experience greater stretch beyond that during normal respiration [4,5]. Mechanical stretches regulate airway remodeling, and the high pressures associated with enhanced ventilation in vivo have been shown to modulate airway gene expression [6,7]. It has been demonstrated that mechanical stretch in vitro regulates epithelial signaling [8], gene expression [8], and pulmonary functions [9,10]. It has been shown that asthma attacks can trigger deep inspirations with increases in amplitude and frequency and that the resulting hyperstretch tends to worsen the airway obstruction [11,12]. Ex vivo hyperstretching (2.56of basal tone) of human bronchi isolated from patients can cause myogenic and pulmonary inflammatory responses (e.g., epithelial release of leukotrienes)

Methods

Results

Conclusion