title: Differential MSC activation leads to distinct mononuclear leukocyte binding mechanisms.
abstract: Advances in the field of Multipotent Mesenchymal Stromal cell (MSC) biology have demonstrated that MSCs can improve disease outcome when 'activated' to exert immunomodulatory effects. However, the precise mechanisms modulating MSC-immune cells interactions remain largely elusive. In here, we activated MSC based on a recent polarization paradigm, in which MSCs can be polarized towards a pro- or anti-inflammatory phenotype depending on the Toll-like receptor stimulated, to dissect the mechanisms through which MSCs physically interact with and modulate leukocytes in this context. Our data show that MSCs activated through the Toll-like receptor (TLR) 4 pathway increased VCAM-1 and ICAM-1 dependent binding of leukocytes. On the other hand, TLR3 stimulation strongly increases leukocytes affinity to MSC comparatively, through the formation of cable-like hyaluronic acid structures. In addition, TLR4 activation elicited secretion of pro-inflammatory mediators by MSCs, whereas TLR3-activated MSCs displayed a milder pro-inflammatory phenotype, similar to inactivated MSCs. However, the differently activated MSCs maintained their ability to suppress leukocyte activation at similar levels in our in vitro model, and this immunomodulatory property was shown here to be partially mediated by prostaglandin. These results reinforce the concept that alternate activation profiles control MSC responses and may impact the therapeutic use of MSCs.
authors.affiliation: Department of Pediatric Surgery, University of Texas Medical School at Houston, 6431 Fannin St., MSB 5.233, Houston, TX, USA 77030.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Kota
authors.affiliation: Department of Pediatric Surgery, University of Texas Medical School at Houston, 6431 Fannin St., MSB 5.233, Houston, TX, USA 77030.
authors.forename: Bryan
authors.initials: B
authors.lastname: DiCarlo
authors.affiliation: Department of Pediatric Surgery, University of Texas Medical School at Houston, 6431 Fannin St., MSB 5.233, Houston, TX, USA 77030.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Hetz
authors.affiliation: Department of Pediatric Surgery, University of Texas Medical School at Houston, 6431 Fannin St., MSB 5.233, Houston, TX, USA 77030.
authors.forename: Philippa
authors.initials: P
authors.lastname: Smith
authors.affiliation: Department of Pediatric Surgery, University of Texas Medical School at Houston, 6431 Fannin St., MSB 5.233, Houston, TX, USA 77030.
authors.forename: Charles S
authors.initials: CS
authors.lastname: Cox
authors.affiliation: Department of Pediatric Surgery, University of Texas Medical School at Houston, 6431 Fannin St., MSB 5.233, Houston, TX, USA 77030.
authors.forename: Scott D
authors.initials: SD
authors.lastname: Olson
mesh_terms: D002450:Cell Communication / Q000502:physiology*; D002454:Cell Differentiation / Q000502:physiology*; D002478:Cells, Cultured; D006801:Humans; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000378:metabolism / Q000502:physiology*; D059630:Mesenchymal Stem Cells / Q000378:metabolism / Q000502:physiology*; D051196:Toll-Like Receptor 3 / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
chemical_list: C495345:TLR4 protein, human; D051196:Toll-Like Receptor 3; D051197:Toll-Like Receptor 4; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1