Molecular Mechanisms of Immunomodulation Properties of Mesenchymal Stromal Cells: A New Insight into the Role of ICAM-1

Abstract

Mesenchymal stromal cells (MSC) control excessive inflammation and create a microenvironment for tissue repair protecting from chronic inflammation and tissue fibrosis. We examined the molecular mechanisms of MSC immunomodulatory function in mixed cultures of human adipose-derived MSC with lymphocytes. Our data show that MSC promote unstimulated lymphocyte survival potentially by an increase in antigen presentation. Under inflammatory conditions, mimicked by stimulation of TCR in lymphocytes, MSC suppress activation and proliferation of stimulated T cells. Immunosuppression is accompanied by downregulation of IL-2Rα that negatively affects the survival of activated T cells. MSC upregulate transcription of indolamine-2,3-dioxygenase (IDO) and inducible NO synthase (iNOS), which generate products negatively affecting T cell function. Both MSC and lymphocytes dramatically increase the surface ICAM-1 level in mixed cultures. Antibody-mediated blockage of surface ICAM-1 partially releases MSC-mediated immune suppression in vitro. Our data suggest that MSC have cell-intrinsic molecular programs depending on the inflammatory microenvironment. We speculate that MSC sense soluble factors and respond by surface ICAM-1 upregulation. ICAM-1 is involved in the control of T cell activation leading to immunosuppression or modest stimulation depending on the T cell status. Immunomodulation by MSC ranging from support of naive T cell survival to immunosuppression of activated T cells may affect the tissue microenvironment protecting from aberrant regeneration.

The Phenotype and Secretory Activity of Adipose-Derived Mesenchymal Stem Cells (ASCs) of Patients with Rheumatic Diseases

“…The adhesion molecules ICAM-1 and VCAM-1 regulate the migration of MSCs and provide their interaction with co-operating immune cells, making them indispensable for MSC-mediated immunosuppression [42,43]. Similar to other reports [18], we failed to observe single VCAM-1 bearing ASCs, found mostly single positive ICAM-1 cells and, less frequently, cells co-expressing both of these molecules (Figure 2A).…”

Substrate-independent immunomodulatory characteristics of mesenchymal stem cells in three-dimensional culture

“…Studies have revealed that, although cell replacement has an important role in MSC therapy for some diseases, the ultimate therapeutic effect is predominantly an outcome of immunomodulatary capacity derived from MSCs, which react with immune system [ 4 , 5 ]. This immunomodulatary capacity in MSC therapy primarily presents as immunosuppression in animal models and human studies [ 4 , 6 ]. Based on these two major characteristics, MSCs are potentially useful for tissue repair and regeneration in stem cell therapy.…”

Potential methods for improving the efficacy of mesenchymal stem cells in the treatment of inflammatory bowel diseases

“…It has been demonstrated that ICAM-1 is involved in the regulation of immune responses, mediating cell differentiation and development, and is closely related to lymphocyte homing and recycling. 65 They found that transplantation of ICAM-1overexpressing MSCs not only alleviated colonic inflammation and regulated T cell subpopulations more obviously, but also mediated a higher number of MSCs homing to the colon and spleen of the mouse model of IBD. 64 MicroRNAs are a family of endogenous non-coding RNAs, consisting of 22-24 bp in length.…”