title: Soluble molecules are key in maintaining the immunomodulatory activity of murine mesenchymal stromal cells.
abstract: Mesenchymal stromal cells (MSCs) possess both immuno-privileged and immuno-inhibitory properties that contribute to their therapeutic effects. Ex vivo expansion is required to obtain sufficient cells for therapy, but might also alter their immunological properties. To date there has been no systematic study of MSC immunobiology during extended culture. Here, we demonstrate that both immuno-privilege and immunosuppressive properties of MSCs change with increasing passage. We demonstrate that although MSCs exhibit powerful immunosuppressive effects through secretion of transforming growth factor-β (TGF-β) and induction of interleukin-10, these effects are diminished by a concomitant increase in MSC immunogenicity. Interferon-γ treatment for 3 days induced extendedly cultured MSCs to express significantly higher levels of major histocompatibility complex class I. In vivo, this results in cells that induce significant delayed-type hypersensitivity reactions in allogeneic recipients. Importantly, these effects are alleviated by isolation of the transplanted MSCs using a semi-permeable barrier. Under these conditions, even MSCs cultured through as many as 14 passages still exhibit immuno-inhibitory effects in vivo. Furthermore, the levels of anti-inflammatory molecule TGF-β secreted by MSCs were maintained in the extended culture. These data shed light on the variable results of allogeneic MSCs in transplantation and suggest alternative strategies for prolonging the effect of allogeneic MSCs in cell-based therapy.
authors.affiliation: Department of Oral & Maxillofacial Surgery, Faculty of Dentistry, National University of Singapore, Singapore.
authors.forename: Hua
authors.initials: H
authors.lastname: Liu
authors.forename: Kai
authors.initials: K
authors.lastname: Lu
authors.forename: Paul Anthony
authors.initials: PA
authors.lastname: MacAry
authors.forename: Kok Loon
authors.initials: KL
authors.lastname: Wong
authors.forename: Alexis
authors.initials: A
authors.lastname: Heng
authors.forename: Tong
authors.initials: T
authors.lastname: Cao
authors.forename: David Michael
authors.initials: DM
authors.lastname: Kemeny
mesh_terms: D000818:Animals; D018929:Cell Culture Techniques; D003470:Culture Media / Q000737:chemistry / Q000378:metabolism; D016207:Cytokines / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism*; D005260:Female; D015395:Histocompatibility Antigens Class I / Q000276:immunology / Q000378:metabolism; D006968:Hypersensitivity, Delayed / Q000276:immunology; D007155:Immunologic Factors / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism*; D007371:Interferon-gamma / Q000276:immunology; D016753:Interleukin-10 / Q000276:immunology / Q000378:metabolism; D059630:Mesenchymal Stem Cells / Q000276:immunology* / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D012995:Solubility; D016212:Transforming Growth Factor beta / Q000276:immunology / Q000378:metabolism
chemical_list: D003470:Culture Media; D016207:Cytokines; D015395:Histocompatibility Antigens Class I; D007155:Immunologic Factors; D016212:Transforming Growth Factor beta; D016753:Interleukin-10; D007371:Interferon-gamma