Abstract
Mesenchymal stromal cells (MSCs) can potently regulate the functions of immune cells and are being investigated for the management of inflammatory diseases. Toll-like receptor 3 (TLR3)-stimulated human MSCs (hMSCs) exhibit increased migration and chemotaxis within and toward damaged tissues. However, the regulatory mechanisms underlying these migratory activities are unclear. Therefore, we analyzed the migration capability and gene expression profiles of TLR3-stimulated hMSCs using RNA-Seq, wound healing, and transwell cell migration assay. Along with increased cell migration, the TLR3 stimulation also increased the expression of cytokines, chemokines, and cell migration-related genes. The promoter regions of the latter showed an enrichment of putative motifs for binding the transcription factors forkhead box O1 (FOXO1), FOXO3, NF-κB (NF-κB1), and RELA proto-oncogene and NF-κB subunit. Of note, FOXO1 inhibition by the FOXO1-selective inhibitor AS1842856 significantly reduced both migration and the expression of migration-related genes. In summary, our results indicate that TLR3 stimulation induces hMSC migration through the expression of FOXO1-activated genes.
Highlights
Mesenchymal stromal cells (MSCs) can potently regulate the functions of immune cells and are being investigated for the management of inflammatory diseases
To study the effects of Toll-like receptor 3 (TLR3) stimulation on human MSCs (hMSCs), we incubated them with poly(I:C) for 4 h
Flow cytometry expression analysis of the typical MSC-related surface antigens showed that both the control hMSCs and TLR3-stimulated hMSCs were positive for CD29, CD44, CD73, and CD105 and negative for the hematopoietic lineage markers CD31, CD34, CD45, and HLA-DR after 6 passages (Fig. 1B)
Summary
Mesenchymal stromal cells (MSCs) can potently regulate the functions of immune cells and are being investigated for the management of inflammatory diseases. We analyzed the migration capability and gene expression profiles of TLR3-stimulated hMSCs using RNA-Seq, wound healing, and transwell cell migration assay. Our results indicate that TLR3 stimulation induces hMSC migration through the expression of FOXO1-activated genes. 5 Present address: Wide River Institute of Immunology, Seoul National University College of Medicine, Hongcheon 25159, Republic of Korea. MSCs play a role as immune modulators by secreting soluble factors and regulating immune cells [7,8,9,10]. These immunomodulatory properties can be used for the treatment of inflammatory diseases such as autoimmuneinduced inflammatory bowel diseases and graft versus host disease [11]. Several studies have suggested that the immunomodulatory properties of MSCs contribute to their beneficial therapeutic effects [12,13,14,15,16]
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