Abstract
Mesenchymal stromal cells (MSCs) constitute the cell type more frequently used in many regenerative medicine approaches due to their exclusive immunomodulatory properties, and they have been reported to mediate profound immunomodulatory effects in vivo. Nevertheless, MSCs do not express essential adhesion molecules actively involved in cell migration, a phenotypic feature that hampers their ability to home inflamed tissues following intravenous administration. In this study, we investigated whether modification by fucosylation of murine AdMSCs (mAdMSCs) creates Hematopoietic Cell E-/L-selectin Ligand, the E-selectin-binding CD44 glycoform. This cell surface glycan modification of CD44 has previously shown in preclinical studies to favor trafficking of mAdMSCs to inflamed or injured peripheral tissues. We analyzed the impact that exofucosylation could have in other innate phenotypic and functional properties of MSCs. Compared to unmodified counterparts, fucosylated mAdMSCs demonstrated higher in vitro migration, an altered secretome pattern, including increased expression and secretion of anti-inflammatory molecules, and a higher capacity to inhibit mitogen-stimulated splenocyte proliferation under standard culture conditions. Together, these findings indicate that exofucosylation could represent a suitable cell engineering strategy, not only to facilitate the in vivo MSC colonization of damaged tissues after systemic administration, but also to convert MSCs in a more potent immunomodulatory/anti-inflammatory cell therapy-based product for the treatment of a variety of autoimmune, inflammatory, and degenerative diseases.
Highlights
Mesenchymal stromal cells (MSCs) are a heterogeneous multipotent progenitor cell population found in almost all adult tissues throughout the body
Murine AdMSCs were resuspended at 2 × 107 cells/ml in fucosyltransferase VII (FTVII) reaction buffer composed of Hanks Balanced Salt Solution (HBSS; without Ca2+/Mg2+; Lonza, Basel, Switzerland) containing 30 μg/ml FTVII (R&D Systems), 20 mM HEPES
Negative controls including murine AdMSCs (mAdMSCs) treated with GDP-fucose alone (i.e., GDP-fuc-mAdMSCs, Figure 1B) and mAdMSCs treated with FTVII alone (i.e., FTVIImAdMSCs, Figure 1C) neither showed HECA452 nor mE-IgG binding
Summary
Mesenchymal stromal cells (MSCs) are a heterogeneous multipotent progenitor cell population found in almost all adult tissues throughout the body. MSCs lack expression of ligands for E-selectin, such as sialofucosylated PSGL-1, CD43, and CD44 glycoforms, molecules called cutaneous lymphocyte antigen (CLA), CD43E, and Hematopoietic Cell E-/L-selectin Ligand (HCELL), respectively, Sackstein et al (2008). The absence of these molecular effectors of cell migration hinders the capacity of infused MSCs to extravasate into the inflamed tissues following systemic administration (Kang et al, 2012; Eggenhofer et al, 2014; Abdi et al, 2015), limiting the efficacy of this immunomodulatory cell therapy. It is important to design new cell engineering based-strategies for improving the tissue delivery of MSCs to inflamed tissues
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