Abstract
Granulocyte colony-stimulating factor (G-CSF) can promote the repair of a variety of damaged tissues, but the underlying mechanisms have not yet been fully elucidated. Bone marrow mesenchymal stem cells (BM-MSCs) play an important role in the repair of damaged tissue. The aim of this study was to explore whether pretreating BM-MSCs with G-CSF can promote their ability of homing to the lung after in vitro transplantation via upregulating the CXCR4 expression, potentially markedly increasing the antifibrotic effect of BM-MSCs. The BM-MSCs pretreated with G-CSF were transplanted into a mouse on day 14 after bleomycin injection. The antifibrotic effects of BM-MSCs in mice were tested on day 21 by using pathological examination and collagen content assay. Pretreatment of BM-MSCs with G-CSF significantly promoted their ability of homing to the lung and enhanced their antifibrotic effects. However, knocking down the CXCR4 expression in BM-MSCs significantly inhibited the ability of G-CSF to promote the migration and homing of BM-MSCs to the lung and the resulting antifibrotic effects. We also found that G-CSF significantly increased the CXCR4 expression and AKT phosphorylation in BM-MSCs, and the AKT pathway inhibitor LY294002 significantly diminished the ability of G-CSF to upregulate the CXCR4 expression in BM-MSCs. Pretreatment of BM-MSCs with G-CSF promotes the homing of BM-MSCs to the lung via upregulating the CXCR4 expression, leading to a marked increase in the antifibrotic effects of BM-MSCs. This study provides new avenues for the application of BM-MSCs in the repair of different tissues.
Highlights
Idiopathic pulmonary fibrosis (IPF) is a disease characterized by diffuse interstitial inflammation and fibrosis, which is typified by fibroblast proliferation and massive extracellular matrix deposition [1]
The degree of pulmonary fibrosis was significantly reduced in the 3 × 106/mL and 1 × 107/mL bone marrow mesenchymal stem cells (BM-MSCs) groups compared with the BLM group (P < 0 05, Figures 1(a)–1(e)), but no antifibrotic effect was observed in the 1 × 106 cells/mL bone marrow (BM)-MSC groups
The degree of pulmonary fibrosis in G-CSFpretreated BM-MSC groups (3 × 106 and 1 × 107 cells/mL) was lower than untreated BM-MSC groups (3 × 106 and 1 × 107 cells/mL) (P < 0 05, Figures 1(a)–1(e)). These results indicate that pretreatment with Granulocyte colony-stimulating factor (G-CSF) could enhance the antifibrotic effect of BM-MSCs
Summary
Idiopathic pulmonary fibrosis (IPF) is a disease characterized by diffuse interstitial inflammation and fibrosis, which is typified by fibroblast proliferation and massive extracellular matrix deposition [1]. With the progress in regenerative medicine and tissue engineering, cell-based therapies are currently under investigation. Recent studies have suggested that bone marrow (BM) cells may be a reservoir of stem cells useful for tissue regeneration [3, 4]. BM-derived stem cells consist mainly of haematopoietic stem cells (HSCs), bone marrow mesenchymal stem cells (BM-MSCs), and endothelial progenitor cells (EPCs). MSCs are currently the most popular cell type for tissue-engineered stem cell applications. Studies have shown that MSCs can promote tissue repair via paracrine signals or by directly differentiating into substitute functional cells of the damaged tissue [5]. The clinical application of MSCs has made significant breakthroughs in the treatment of various diseases, including respiratory diseases, cardiovascular diseases, cirrhosis, and neurological diseases [6,7,8,9]
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