Intercellular adhesion molecule-1 enhances the therapeutic effects of MSCs in a dextran sulfate sodium-induced colitis models by promoting MSCs homing to murine colons and spleens

Abstract

Abstract Background To investigate the therapeutic effect of intercellular adhesion molecule (ICAM)-1-modified mesenchymal stem cells (MSCs) in a mouse model of inflammatory bowel disease (IBD) induced by dextran sulfate sodium. Methods Primary MSCs and ICAM-1-overexpressing MSCs (C3 cells) were generated in vitro. The IBD mouse model was induced with drinking water containing dextran sulfate sodium for 7 days. For stem cell therapy, mice were randomly assigned to six experimental groups: the control group, IBD group, primary MSC group, C3 group, C3-vector group, and C3-ICAM-1 group. Mice were given a single injection of 1 × 106 primary MSCs or gene-modified MSCs via the tail vein on day 3 of DDS administration. The general conditions of the mice in each group were observed. Additionally, the pathological changes in the colon were observed and scored. Primary MSCs and gene-modified MSCs were stained with the fluorescent dye CM-DIL before injection into the tail vein of mice. The distribution of infused cells in IBD mice was observed in frozen sections. Mechanistically, the polarization of Th1, Th2, Th17, and regulatory T cells (Tregs) in the spleen was determined by flow cytometry. Moreover, the mRNA expression levels of IBD-related immune factors in splenocytes were measured by quantitative PCR. Results A single injection of MSCs promoted general recovery and reduced pathological damage in IBD mice. Additionally, ICAM-1-overexpressing MSCs had stronger therapeutic effects than ICAM-1low MSCs. Furthermore, the in vivo distribution analysis results indicated that a higher number of ICAM-1-overexpressing MSCs homed to the colon and spleen of IBD mice. Moreover, the delivery of ICAM-1 overexpressing MSCs decreased the numbers of Th1 and Th17 cells but increased the number of Tregs in the spleen of IBD mice. The quantitative PCR analysis results revealed that an infusion of ICAM-1-overexpressing MSCs influenced the expression of spleen-derived immune factors by remarkably reducing the mRNA levels of IFN-γ and IL-17A and increasing the mRNA level of Foxp3. Conclusions Our results demonstrate that ICAM-1-modified mesenchymal stem cells (MSCs) remarkably alleviate inflammatory damage in IBD mice by promoting MSC homing to the target and immune organs. The findings suggest that ICAM-1 is required to maintain the therapeutic effects of MSCs in IBD treatment and identified a novel role of ICAM-1 in inflammatory diseases.

Keywords

• Inflammatory bowel disease
• Mesenchymal stem cells
• Intercellular cell adhesion molecule-1
• Homing