title: Human mesenchymal stem cells induce T cell anergy and downregulate T cell allo-responses via the TH2 pathway: relevance to tissue engineering human heart valves.
abstract: To generate an ''off the shelf'' tissue-engineered heart valve, the cells would need to be of allogeneic origin. Here, we report the possibility of using human bone marrow-derived mesenchymal stem cells (MSCs) as a suitable allogeneic cell source for tissue-engineered heart valves. Proliferative responses of primary and primed CD4+ T cells to allogeneic MSCs were examined. A protein microarray system was used to detect soluble factors from supernatants collected from the T cell assays. MSCs are poor stimulators of primary and primed CD4+ T cell proliferation, despite provision of B7-1 trans-co-stimulation. MSCs not only directly inhibited primary and primed T cell responses to allogeneic peripheral blood mononuclear cells (PBMCs), but 24-h pre-culture of T cells with MSCs suppressed subsequent T cell proliferative responses to allogeneic PBMCs in a contact-dependent manner. Analysis of supernatants revealed a distinctly different cytokine profile after co-culture of T cells with MSCs than with PBMCs or endothelial cells. Pro-inflammatory Th1 cytokines interleukin (IL)-1alpha and beta, interferon (IFN)gamma, and tumor necrosis factor (TNF)alpha were downregulated, whereas, anti-inflammatory Th2 cytokines IL-3, IL-5, IL-10, and IL-13 and the Th2 chemokine I-309, a chemoattractant for regulatory T cells, were upregulated. Further analysis revealed that after co-culture with MSCs, the T cells exhibited a regulatory phenotype (CD4+ CD25(lo) CD69(lo) FoxP3+). MSCs downregulate T cell responses through direct contact and secretion of anti-inflammatory and tolerogenic cytokines, which may involve the recruitment of regulatory T cells. This implies that allogeneic MSCs could be a suitable cell source for tissue engineering a heart valve.
authors.affiliation: Heart Science Centre, National Heart and Lung Institute, Imperial College London at Harefield Hospital, Harefield, Middlesex, United Kingdom. p.batten@imperial.ac.uk
authors.forename: Puspa
authors.initials: P
authors.lastname: Batten
authors.forename: Padmini
authors.initials: P
authors.lastname: Sarathchandra
authors.forename: Joseph W
authors.initials: JW
authors.lastname: Antoniw
authors.forename: Szun Szun
authors.initials: SS
authors.lastname: Tay
authors.forename: Mark W
authors.initials: MW
authors.lastname: Lowdell
authors.forename: Patricia M
authors.initials: PM
authors.lastname: Taylor
authors.forename: Magdi H
authors.initials: MH
authors.lastname: Yacoub
mesh_terms: D002478:Cells, Cultured; D017635:Clonal Anergy / Q000276:immunology*; D006351:Heart Valves / Q000276:immunology*; D006801:Humans; D007518:Isoantibodies / Q000096:biosynthesis*; D059630:Mesenchymal Stem Cells / Q000502:physiology*; D018418:Th2 Cells / Q000276:immunology* / Q000378:metabolism; D023822:Tissue Engineering
chemical_list: D007518:Isoantibodies