Induced Pluripotent Stem Cells Inhibit Bleomycin-Induced Pulmonary Fibrosis in Mice through Suppressing TGF-β1/Smad-Mediated Epithelial to Mesenchymal Transition

Abstract

Pulmonary fibrosis is a progressive and irreversible fibrotic lung disorder with high mortality and few treatment options. Recently, induced pluripotent stem (iPS) cells have been considered as an ideal resource for stem cell-based therapy. Although, an earlier study demonstrated the therapeutic effect of iPS cells on pulmonary fibrosis, the exact mechanisms remain obscure. The present study investigated the effects of iPS cells on inflammatory responses, transforming growth factor (TGF)-β1 signaling pathway, and epithelial to mesenchymal transition (EMT) during bleomycin (BLM)-induced lung fibrosis. A single intratracheal instillation of BLM (5 mg/kg) was performed to induce pulmonary fibrosis in C57BL/6 mice. Then, iPS cells (c-Myc-free) were administrated intravenously at 24 h following BLM instillation. Three weeks after BLM administration, pulmonary fibrosis was evaluated. As expected, treatment with iPS cells significantly limited the pathological changes, edema, and collagen deposition in lung tissues of BLM-induced mice. Mechanically, treatment with iPS cells obviously repressed the expression ratios of matrix metalloproteinase-2 (MMP-2) to its tissue inhibitor -2 (TIMP-2) and MMP-9/TIMP-1 in BLM-induced pulmonary tissues. In addition, iPS cell administration remarkably suppressed BLM-induced up-regulation of pulmonary inflammatory mediators, including tumor necrosis factor-α, interleukin (IL)-1β, IL-6, inducible nitric oxide synthase, nitric oxide, cyclooxygenase-2 and prostaglandin E2. We further demonstrated that transplantation of iPS cells markedly inhibited BLM-mediated activation of TGF-β1/Mothers against decapentaplegic homolog 2/3 (Smad2/3) and EMT in lung tissues through up-regulating epithelial marker E-cadherin and down-regulating mesenchymal markers including fibronectin, vimentin and α-smooth muscle actin. Moreover, in vitro, iPS cell-conditioned medium (iPSC-CM) profoundly inhibited TGF-β1-induced EMT signaling pathway in mouse alveolar epithelial type II cells (AECII). Collectively, our results suggest that transplantation of iPS cells could suppress inflammatory responses, TGF-β1/Smad2/3 pathway and EMT during the progression of BLM-induced pulmonary fibrosis, providing new useful clues regarding the mechanisms of iPS cells in the treatment for this disease.

Inhibition of EZH2 prevents acute respiratory distress syndrome (ARDS)-associated pulmonary fibrosis by regulating the macrophage polarization phenotype

“…It is well known that TGF-β1 is a key cytokine leading to EMT and TGF-β1overexpression is associated with poorer prognosis in ARDS [23,33] .The downstream effects of TGF-β1 are mediated by Smad2/3, while Smad7 can bind TGF-βR1and prevent TGF-β-associated Smad signaling [33] . It has been demonstrated that TGF-β1induced EMT in alveolar epithelial cells both in vivo and in vitro via Smad2/3 activation [34,35] . In parallel with these observations, we found that expression of TGF-β1, TGF-βR1, p-Smad2 were all upregulated in the brotic lung tissue while Smad7 was downregulated.…”

Astragaloside IV Improves Bleomycin-Induced Pulmonary Fibrosis in Rats by Attenuating Extracellular Matrix Deposition

“…Pulmonary fibrosis (PF), characterized by exaggerated accumulation of extracellular matrix (ECM) proteins, is a progressive and irreversible fatal lung disease with a median survival time less than 3 years ( King et al, 2011 ; Warsinske et al, 2016 ; Li and Kan, 2017 ). Although the etiology of PF is still unclear, emerging studies have shown that some special type of cells and cytokines play vital roles in the process of PF ( Li et al, 2014b ; Zhou et al, 2016 ). Several treatment strategies including the anti-fibrinolytic composition, glucocorticoids, and anti-oxidants have been proved to be effective in the laboratory studies or human PF.…”

Combination Therapy Targeting BCL6 and Phospho-STAT3 Defeats Intratumor Heterogeneity in a Subset of Non–Small Cell Lung Cancers

“…Because the HBEC PKM cell line shows mesenchymal-like behavior (6), the SMAD2/3 down-regulated subpopulation was not expected (26,27). Thus, we next chose to investigate if alterations in SMAD2/3 signaling are genuinely oncogene-related.…”