G-CSF Treats Fibrosis Through Stem Cell Recruitment, Mouse Study Shows
The protein granulocyte-colony stimulating factor (G-CSF) inhibited fibrosis in a mouse model of pulmonary fibrosis, a new study shows. The data suggests this effect is driven, in part, by stem cells from the bone marrow being recruited to the lungs.
The study, “G-CSF Inhibits Pulmonary Fibrosis by Promoting BMSC Homing to the Lungs via SDF-1/CXCR4 Chemotaxis,” was published in the journal Nature Scientific Reports.
Mesenchymal stem cells (MSCs) are a type of multipotent cell, meaning they can differentiate into other cell types. These cells also participate in regulating immunity and promoting tissue repair. As such, they have been suggested as a promising treatment strategy for pulmonary fibrosis.
The most common therapeutic strategy with MSCs is to extract them from a person, multiply them in a lab setting, and then re-insert them to the person. However, this strategy is complex and costly, so its utility in a clinical setting is limited.
G-CSF is a signaling protein. Among its properties, G-CSF can prompt MSCs in the bone marrow — referred to as bone marrow MSCs (BMSCs) — to mobilize to other parts of the body.
“At present, the potential therapeutic effect of G-CSF mobilizes autologous [cells from the same person] BMSCs in the treatment of pulmonary fibrosis remains unclear,” the researchers wrote. “The aim of our study was to investigate whether mobilization of autologous BMSCs by G-CSF could inhibit pulmonary fibrosis, and further explore the mechanism of action.”
Researchers used a mouse model of pulmonary fibrosis, in which fibrosis was induced with the chemotherapy bleomycin. Some of the mice were treated with G-CSF, at doses of 40 or 60 micrograms (mcg) per kilogram injected under the skin.
Mice were treated with G-CSF either immediately after bleomycin administration (preventive G-CSF treatment) or two weeks after bleomycin administration (therapeutic G-CSF treatment).
Mice treated with 40 mcg/kg G-CSF, either preventively or therapeutically, had significantly less severe pulmonary fibrosis, as assessed by the Ashcroft score. The treatment also significantly reduced the production of collagen, a major component of fibrosis (scar) tissue.
Preventive treatment with 60 mcg/kg G-CSF did not reduce pulmonary fibrosis and this dose was not further assessed. According to the team, this result indicated that “a relative low dose was critical for the antifibrotic effect of G-CSF.”
Regarding MSCs, there were significantly more MSCs in the lungs of mice treated with G-CSF compared to those that were not treated.
Furthermore, when researchers injected BMSCs into mice, a higher proportion of the injected BMSCs were detectable in the lungs of mice pre-treated with G-CSF, suggesting that G-CSF enhanced BMSC migration to lung tissues.
“The results showed that more G-CSF-pretreated BMSCs than nontreated BMSCs entered the lung tissue,” researchers wrote. “Therefore, we propose that G-CSF promoted BMSCs homing to the lung tissue.” This increase of MSCs in lung tissue is, presumably, at least partially responsible for the therapeutic effects of G-CSF, the team believes.
Using chemical inhibitors, the researchers further demonstrated that the molecular mechanism of this G-CSF-mediated BMSC recruitment to the lungs involves the signaling protein stromal cell-derived factor-1 (SDF-1), which acts by binding to a protein receptor called C-X-C motif chemokine receptor 4 (CXCR4).
The team also conducted preliminary tests to determine whether G-CSF treatment had an effect on how BMSCs affect fibroblasts, which is a type of cell that drives fibrosis. While BMSCs reduced fibroblast growth and proliferation, G-CSF treatment did not change this effect significantly.
“In present study, we concluded that G-CSF exerted antifibrotic effects in bleomycin-induced lung fibrosis, in part by promoting BMSCs homing to injured lung tissues via SDF-1/CXCR4 chemotaxis,” the researchers wrote.
“These findings provide insights into the therapeutic effect of G-CSF treatment in lung fibrosis and underline that BMSCs may act as an autologous cell resource for developing treatments of interstitial lung disease,” they concluded.