Abstract
Lung diseases are a major cause of global morbidity and mortality that are treated with limited efficacy. Recently stem cell therapies have been shown to effectively treat animal models of lung disease. However, there are limitations to the translation of these cell therapies to clinical disease. Studies have shown that delayed treatment of animal models does not improve outcomes and that the models do not reflect the repeated injury that is present in most lung diseases. We tested the efficacy of amnion mesenchymal stem cells (AM-MSC), bone marrow MSC (BM-MSC) and human amniotic epithelial cells (hAEC) in C57BL/6 mice using a repeat dose bleomycin-induced model of lung injury that better reflects the repeat injury seen in lung diseases. The dual bleomycin dose led to significantly higher levels of inflammation and fibrosis in the mouse lung compared to a single bleomycin dose. Intravenously infused stem cells were present in the lung in similar numbers at days 7 and 21 post cell injection. In addition, stem cell injection resulted in a significant decrease in inflammatory cell infiltrate and a reduction in IL-1 (AM-MSC), IL-6 (AM-MSC, BM-MSC, hAEC) and TNF-α (AM-MSC). The only trophic factor tested that increased following stem cell injection was IL-1RA (AM-MSC). IL-1RA levels may be modulated by GM-CSF produced by AM-MSC. Furthermore, only AM-MSC reduced collagen deposition and increased MMP-9 activity in the lung although there was a reduction of the pro-fibrogenic cytokine TGF-β following BM-MSC, AM-MSC and hAEC treatment. Therefore, AM-MSC may be more effective in reducing injury following delayed injection in the setting of repeated lung injury.
Highlights
Lung diseases such as chronic obstructive pulmonary disease (COPD) and lung fibrosis are a major cause of global morbidity and mortality
We demonstrated that human amniotic epithelial cells reduced pro-inflammatory and pro-fibrogenic cytokines, increased matrix metallo-proteinase (MMP) function while reducing tissue inhibitors of MMP (TIMP) and thereby promoting a collagen degrading environment in the injured lung [10]
We examined the effects of stem cells in a clinically more relevant model of repeated lung injury where mice were instilled intra-nasally with two doses of 0.15 mg bleomycin and cells injected 3 days later
Summary
Lung diseases such as chronic obstructive pulmonary disease (COPD) and lung fibrosis are a major cause of global morbidity and mortality. Therapeutic options that are available currently including bronchodilators and immunosuppressive agents do not significantly change the chronic course of these diseases This is in part due to the limited ability of these agents to attenuate the continuing injury and death of structural cells that are essential for gas exchange. Adult stem cell-based therapies for lung diseases have demonstrated potential benefits in animal models. These models range from bleomycin, oleic acid and ventilator-induced lung injury [1][2],[3],[4]. Mesenchymal stem cells (MSC) from bone marrow (BM-MSC) and umbilical cord (UC-MSC) have been shown to reduce inflammation and fibrosis in bleomycin induced lung injury [1,5]. In addition to KGF, tumor necrosis factor alpha inducible gene-6 (TSG-6) [7] and interleukin-1 receptor antagonist (IL-1RA) are among the growing list of molecules that have been shown to mediate the anti-inflammatory functions of BM-MSC [8]
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