Anti-Inflammatory Effects of Adult Stem Cells in Sustained Lung Injury: A Comparative Study

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.

Effect of Fetal Membrane-Derived Mesenchymal Stem Cell Transplantation in Rats With Acute and Chronic Pancreatitis

“…42,43 Furthermore, a first-in-human clinical trial of FM-MSC transplantation for nine patients with steroid-refractory acute GVHD demonstrated that the FM-MSCs appeared safe for intravenous infusion and the overall response rate in severe refractory acute GVHD was similar to that observed when using bone marrow-derived MSCs. 44 This is encouraging because the collection of AMSCs involves procedures less invasive than those used for obtaining MSCs from bone marrow or adipose tissue from donors.…”

Effects of human amnion–derived mesenchymal stromal cell transplantation in rats with radiation proctitis

“…It has been demonstrated that intravenous infusion of human AMSCs ameliorates inflammation and fibrosis in the lung induced by bleomycin in mice [43] and reduces liver fibrosis induced by carbon tetrachloride administration in mice [44].…”

A novel segmental challenge model for bleomycin-induced pulmonary fibrosis in sheep

“…The hydroxyproline assay was used to extrapolate the collagen content and concentration of each segment, as described previously [29,30]. Briefly, frozen lung tissues from each segment were lyophilized to dry weight, hydrolyzed in 6M HCl, and assessed for hydroxyproline content by measuring the absorbance of reconstituted samples (in 0.1M HCl) at 558 nm using a Beckman DU-64 spectrophotometer (Beckman Coulter Inc, Brea, CA).…”