Distal airway stem cells ameliorate bleomycin-induced pulmonary fibrosis in mice

Yun Shi,Min Chen,Mingqing Dong,Faguang Jin,Yongheng Gao,Wangping Li,Wei Zuo,Hongwei Lin,Yueqing Zhou,Luyao Han

doi:10.1186/s13287-019-1257-2

Abstract

BackgroundIdiopathic pulmonary fibrosis is characterized by loss of lung epithelial cells and inexorable progression of fibrosis with no effective and approved treatments. The distal airway stem/progenitor cells (DASCs) have been shown to have potent regenerative capacity after lung injury. In this work, we aimed to define the role of mouse DASCs (mDASCs) in response to bleomycin-induced lung fibrosis in mice.MethodsThe mDASCs were isolated, expanded in vitro, and labeled with GFP by lentiviral infection. The labeled mDASCs were intratracheally instilled into bleomycin-induced pulmonary fibrosis mice on day 7. Pathological change, collagen content, α-SMA expression, lung function, and mortality rate were assessed at 7, 14, and 21 days after bleomycin administration. Tissue section and direct fluorescence staining was used to show the distribution and differentiation of mDASCs in lung.ResultsThe transplanted mDASCs could incorporate, proliferate, and differentiate into type I pneumocytes in bleomycin-injured lung. They also inhibited fibrogenesis by attenuating the deposition of collagen and expression of α-SMA. In addition, mDASCs improved pulmonary function and reduce mortality in bleomycin-induced pulmonary fibrosis mice.ConclusionsThe data strongly suggest that mDASCs could ameliorate bleomycin-induced pulmonary fibrosis by promotion of lung regeneration and inhibition of lung fibrogenesis.

Highlights

Idiopathic pulmonary fibrosis is characterized by loss of lung epithelial cells and inexorable progression of fibrosis with no effective and approved treatments
It had been demonstrated that the expression of KRT5 and P63 was the characteristic marker of distal airway stem cells; we found little evidence of KRT5+P63+ cells in the parenchyma of normal mice
The present study firstly demonstrated that the transplantation of mouse DASCs (mDASCs) at the acute injury stage could ameliorate the following fibrosis, improve lung function, Fig. 5 Transplanted mDASCs decreased the collagen content and expression of α-SMA in lungs in bleomycin-induced pulmonary fibrosis mice. a Collagen deposition was assessed by measuring the hydroxyproline content in lung tissue. n = 5

Summary

Introduction

Idiopathic pulmonary fibrosis is characterized by loss of lung epithelial cells and inexorable progression of fibrosis with no effective and approved treatments. The distal airway stem/progenitor cells (DASCs) have been shown to have potent regenerative capacity after lung injury. Idiopathic pulmonary fibrosis (IPF) is an idiopathic interstitial lung disease characterized by loss of lung epithelial cells and inexorable progression of fibrosis, which results in loss of normal lung architecture, respiratory failure, and eventual fatal outcome [1,2,3]. The distal airway stem/progenitor cells (DASCs) expressing basal cell-restricted transcription factor p63 and keratin-5 (KRT5) have been shown to have potent regenerative capacity after lung injury [13,14,15,16].

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