Abstract
BackgroundBone marrow mesenchymal stem cells (BMSC) transfer has been attempted as a therapeutic strategy in experimental lung injury and fibrosis. Reduction of neutrophilic infiltration is one of the mechanisms involved in this effect. However, the mechanisms by which BMSC modulate neutrophil remains unknown.Methods and resultsExposure of mice to bleomycin (BLM) resulted in significant accumulation of cells that express neutrophilic markers Gr-1HighCD11b+Ly-6GHighF4/80―CD115―CD49d―. These cells lacked immunosuppressive activity and could not be defined as myeloid-derived suppressor cells (MDSC). When BMSC were administrated to BLM-treated mice, they tuned the differentiation of Gr-1HighCD11b+ toward Gr-1LowCD11b+ cells. Gr-1LowCD11b+ cells exhibited unsegmented nuclei and expressed F4/80, Ly-6C, CD49d, and CD115 markers. These cells had potent immunosuppressive activity and thus could be defined as monocytic MDSC. As a result of such immunoregulation, BMSC mediated a decrease of pro-inflammatory products and amelioration of lung injury in BLM-treated mice. Further study using antibody array showed increased expression of macrophage colony-stimulating factor (M-CSF) in BMSC-treated mice. Accumulation of Gr-1LowCD11b+ cells in BMSC-treated mice was abrogated in M-CSF neutralizing mice. The beneficial effect of BMSC was independent of the ability of the cells to engraft in lung and in vitro coculture study of BMSC with Gr-1+CD11b+ cells showed that the induction of Gr-1LowCD11b+ cells by BMSC was independent of cell-cell contact.ConclusionsThese results document the generation of Gr-1HighCD11b+ cells in BLM-treated mice, and suggest that BMSC tune the differentiation of Gr-1HighCD11b+ toward Gr-1LowCD11b+ cells and therefore inhibit the progression of BLM-induced lung injury.
Highlights
Bone marrow mesenchymal stem cells (BMSC) transfer has been attempted as a therapeutic strategy in experimental lung injury and fibrosis
It has been shown that G-myeloid-derived suppressor cells (MDSC) accumulate in cystic fibrosis (CF) patients, in patients infected with Pseudomonas aeruginosa and correlate with CF lung disease activity [13]
BMSC attenuate bleomycin-induced lung injury/fibrosis To quantitatively assess the degree of pulmonary edema following BLM treatment, the wet/dry weight ratio of the left lung was measured
Summary
Bone marrow mesenchymal stem cells (BMSC) transfer has been attempted as a therapeutic strategy in experimental lung injury and fibrosis. Pulmonary fibrosis is characterized by epithelial cell injury and hyperplasia, variable degrees of inflammatory cell infiltrate, fibroblast proliferation and accumulation, and deposition of extracellular matrix [1]. G-MDSC are phenotypically and morphologically similar to neutrophils, whereas M-MDSC are similar to monocytes. These cells represent a pathologic state of activation of monocytes and relatively immature neutrophils. It has been shown that G-MDSC accumulate in cystic fibrosis (CF) patients, in patients infected with Pseudomonas aeruginosa and correlate with CF lung disease activity [13]. While the role of MDSC in cancer has been studied in depth, our understanding of their relevance for pulmonary injury/fibrosis has just begun to evolve
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