Study of Bone Marrow and Embryonic Stem Cell-Derived Human Mesenchymal Stem Cells for Treatment of Escherichia coil Endotoxin-Induced Acute Lung Injury in Mice

Mesenchymal stem cells (MSCs) can be derived from multiple tissue sources. However, the optimal source of MSCs for cell-based therapy for acute lung injury (All) is unclear. In the present experiments, we studied bone marrow (BM)-derived and embryonic stem cell-derived human MSC (ES-MSCs) as a therapeutic agent in Escherichia coil endotoxin-induced All in mice. We hypothesized that ES-MSCs would be more potent than BM-MSCs owing to its more primitive source of origin. ALI was induced by the intratracheal instillation of endotoxin at 4 mg/kg into 10-12-week-old C57BL/6 mice with or without BM-MSCs, ESMSCs, or normal human lung fibroblasts as a cellular control. Compared with the endotoxin-injured mice at 48 hours, the administration of ES-MSCs provided results similar to those of BM-MSCs, significantly reducing the influx of white blood cells and neutrophils and decreasing the secretion of the inflammatory cytokines, macrophage inflammatory protein-2 and tumor necrosis factor-a, in the injured alveolus. BM-MSCs also reduced extravascular lung water, a measure of pulmonary edema, by 60% and the total protein levels, a measure of lung permeability, by 66%. However, surprisingly, ES-MSCs did not have these protective effects, which was partially explained by the increased secretion of matrix metallopeptidase 9 by ES-MSCs, an enzyme known to increase lung protein permeability. In conclusion, both BM-MSCs and ESMSCs markedly decreased endotoxin-induced inflammation. However, ES-MSCs did not show any beneficial effect on reducing pulmonary edema and lung protein permeability compared with BM-MSCs, suggesting that not all MSC5 behave in a similar fashion. Our results highlight the need perhaps for a disease-specific potency assay for MSCs.