H19 Overexpression Improved Efficacy of Mesenchymal Stem Cells in Ulcerative Colitis by Modulating the miR-141/ICAM-1 and miR-139/CXCR4 Axes

Ming-Li Zhao,Tao Chen,Xiao Wan,Feng Tian,Teng-Hui Zhang,Wen-Jun Tu

doi:10.1155/2021/7107705

Abstract

Overexpression of C-X-C motif chemokine receptor 4 (CXCR4) and intercellular cell adhesion molecule-1 (ICAM-1) may promote homing of mesenchymal stem cells (MSC). In this study, we treated ulcerative colitis animals with MSC preconditioned with or without H19 and compared the therapeutic effect of MSC and MSC-H19. We evaluated the regulatory relationship of H19 vs. miR-141/miR-139 and miR-141/miR-139 vs. ICAM-1/CXCR4. We established an ulcerative colitis mouse model to assess the effect of MSC and MSC-H19. H19 was found to bind to miR-141 and miR-139. The activity of H19 was strongly decreased in cells c-transfected with miR-141/miR-139 and WT H19. ICAM-1 was confirmed to be targeted by miR-141 and CXCR4 was targeted by miR-139. The H19 expression showed a negative regulatory relationship with the miR-141 and miR-139 expression but a positive regulatory relationship with the ICAM-1 and CXCR4 expression. In summary, the overexpression of H19 in MSC downregulated miR-139 and miR-141, thus increasing the activity of their targets ICAM-1 and CXCR4, respectively, to exhibit therapeutic effects in ulcerative colitis.

Highlights

As a condition of the gastrointestinal tract system, inflammatory bowel disease (IBD) manifests as ulcerative colitis, Crohn’s disease, and persistent inflammation in the stomach
intercellular cell adhesion molecule-1 (ICAM-1) was predicted to be a downstream target of miR-141 (Figure 1(b)), and CXCR4 was predicted to be a downstream target of miR-139 (Figure 1(d))
The luciferase activity was tested in cells cotransfected with control + WT/MUT ICAM-1 compared with cells cotransfected with miR-141 + WT/MUT ICAM-1 (Figure 1(b)) and in cells cotransfected with control + WT/MUT CXCR4 compared with cells cotransfected miR-139 + WT/MUT CXCR4 (Figure 1(d))

Summary

Introduction

As a condition of the gastrointestinal tract system, inflammatory bowel disease (IBD) manifests as ulcerative colitis, Crohn’s disease, and persistent inflammation in the stomach. Mesenchymal stem cells (MSC) are present in many body organs, such as dental pulp, bone marrow, fat, and muscles; MSC are linked to the microvasculature in the entire body as pericytes. These cells may differentiate into different types of mesenchymal cells [3]. MSC possess strong immunomodulatory properties by reducing the proliferation of inflammatory cells as well as the synthesis of cytokines [4]. MSC are presently utilized for the treatment of inflammatory conditions, such as myocarditis, sclerosis, and IBD [5, 6]. While the functions of MSC remain elusive, MSC are used for IBD therapy and have displayed appealing outcomes in animals [7,8,9]

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Results

Conclusion