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

September 26th, 2023

Integrin beta 3-overexpressing mesenchymal stromal cells display enhanced homing and can reduce atherosclerotic plaque — Expression of inflammatory factors in the vascular atherosclerotic plaque. A: Expression of mouse vascular cell adhesion molecule-1 (VCAM-1), intercellular cell adhesion molecule-1 (ICAM-1), and osteopontin (OPN) expression in total tissue lysates of normal and atherosclerotic (AS) aorta analyzed using western blot. GAPDH was used as the internal control. The experiment was repeated thrice with tissues isolated from independent mice; a representative blot is shown; B: Expression levels of various inflammatory factors involved in atherosclerosis analyzed using quantitative real-time polymerase chain reaction of mRNA samples extracted from normal and AS vessels of three independent mice. Data are presented as the mean ± SEM for each group. Fold change represents the expression of each inflammatory factor in AS vessel of a mice fed with high fat diet for 12 wk compared with that in normal blood vessel; C: Representative images of normal and AS vascular sections stained for VCAM1 (red) and ICAM1 (red). The experiment was repeated three times with tissues isolated from independent mice; a representative image is shown. Nuclei were visualized by DAPI staining (blue). Scale bars = 100 mm; D: Representative images of normal and AS vascular sections stained for ICAM1 (red). The experiment was repeated three times with tissues isolated from independent mice; a representative image is shown. Nuclei were visualized by DAPI staining (blue). Scale bars = 100 μm. ^bP < 0.001. AS: Atherosclerotic; OPN: Osteopontin; qRT-PCR: Quantitative real-time polymerase chain reaction; SEM: Standard error of the mean; VCAM-1: Vascular cell adhesion molecule-1; ICAM-1: Intercellular cell adhesion molecule-1. Credit: World Journal of Stem Cells (2023). DOI: 10.4252/wjsc.v15.i9.931

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 (MSCsITGB3) 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 (MSCsGFP) or MSCsITGB3 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, MSCsITGB3 showed significantly faster migration than MSCsGFP. 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 MSCsITGB3, significantly reducing the plaque area. Enzyme-linked immunosorbent assay and quantitative real-time polymerase chain reaction revealed that MSCITGB3 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.

The findings are published in the World Journal of Stem Cells.

More information:
Hai-Juan Hu et al, Integrin beta 3-overexpressing mesenchymal stromal cells display enhanced homing and can reduce atherosclerotic plaque, World Journal of Stem Cells (2023). DOI: 10.4252/wjsc.v15.i9.931

Provided by World Journal of Stem Cells

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