Integrin beta 3-overexpressing mesenchymal stromal cells display enhanced homing and can reduce atherosclerotic plaque

BACKGROUND

Umbilical cord (UC) mesenchymal stem cell (MSC) transplantation is a potential therapeutic intervention for atherosclerotic vascular disease. Integrin beta 3 (ITGB3) promotes cell migration in several cell types. However, whether ITGB-modified MSCs can migrate to plaque sites in vivo and play an anti-atherosclerotic role remains unclear.

AIM

To investigate whether ITGB3-overexpressing MSCs (MSCs^ITGB3) would exhibit improved homing efficacy in atherosclerosis.

METHODS

UC MSCs were isolated and expanded. Lentiviral vectors encoding ITGB3 or green fluorescent protein (GFP) as control were transfected into MSCs. Sixty male apolipoprotein E^-/- mice were acquired from Beijing Vital River Lab Animal Technology Co., Ltd and fed with a high-fat diet (HFD) for 12 wk to induce the formation of atherosclerotic lesions. These HFD-fed mice were randomly separated into three clusters. GFP-labeled MSCs (MSCs^GFP) or MSCs^ITGB3 were transplanted into the mice intravenously via the tail vein. Immunofluorescence staining, Oil red O staining, histological analyses, western blotting, enzyme-linked immunosorbent assay, and quantitative real-time polymerase chain reaction were used for the analyses.

RESULTS

ITGB3 modified MSCs successfully differentiated into the “osteocyte” and “adipocyte” phenotypes and were characterized by positive expression (> 91.3%) of CD29, CD73, and CD105 and negative expression (< 1.35%) of CD34 and Human Leukocyte Antigen-DR. In a transwell assay, MSCs^ITGB3 showed significantly faster migration than MSCs^GFP. ITGB3 overexpression had no effects on MSC viability, differentiation, and secretion. Immunofluorescence staining revealed that ITGB3 overexpression substantially enhanced the homing of MSCs to plaque sites. Oil red O staining and histological analyses further confirmed the therapeutic effects of MSCs^ITGB3, significantly reducing the plaque area. Enzyme-linked immunosorbent assay and quantitative real-time polymerase chain reaction revealed that MSC^ITGB3 transplantation considerably decreased the inflammatory response in pathological tissues by improving the dynamic equilibrium of pro- and anti-inflammatory cytokines.

CONCLUSION

These results showed that ITGB3 overexpression enhanced the MSC homing ability, providing a potential approach for MSC delivery to plaque sites, thereby optimizing their therapeutic effects.

Key Words: Atherosclerosis, Inflammation, Integrin beta 3, Mesenchymal stem cells, Arg-Gly-Asp structure, Umbilical cord

Core Tip: Mesenchymal stem cell (MSC) transplantation is considered a new treatment for atherosclerosis. However, research regarding homing of MSCs to atherosclerotic lesions is insufficient. Here, we transplanted integrin beta 3 (ITGB3)-overexpressing MSCs into a mouse model of atherosclerosis. ITGB3-overexpressing MSCs were more greatly accumulated in atherosclerotic plaques. These MSCs prevented plaque progression by shifting the local cytokine profile. The use of ITGB3-overexpressing MSCs may be a novel tool to treat atherosclerosis.

• Citation: Hu HJ, Xiao XR, Li T, Liu DM, Geng X, Han M, Cui W. Integrin beta 3-overexpressing mesenchymal stromal cells display enhanced homing and can reduce atherosclerotic plaque. World J Stem Cells 2023; 15(9): 931-946
• URL: https://www.wjgnet.com/1948-0210/full/v15/i9/931.htm
• DOI: https://dx.doi.org/10.4252/wjsc.v15.i9.931