Requirement of IFN-gamma-mediated indoleamine 2,3-dioxygenase expression in the modulation of lymphocyte proliferation by human adipose-derived stem cells.
Human adipose-derived mesenchymal stem cells (hASCs) are mesenchymal stem cells (MSCs) with reduced immunogenicity and capability to modulate immune responses. Whereas the immunosuppressive activity of bone marrow-MSCs has received considerable attention during the last few years, the specific mechanisms underlying hASC-mediated immunosuppression have been poorly studied. Recent studies comparing both cell types have reported differences at transcriptional and proteomic levels, suggesting that hASCs and bone marrow-MSCs, while having similarities, are quite different. This suggests that different mechanisms of immunosuppression may apply. Here, we report that hASCs inhibit peripheral blood mononuclear cells (PBMCs), and CD4(+) and CD8(+) T cell proliferation in both cell-cell contact and transwell conditions, which is accompanied by a reduction of proinflammatory cytokines. We demonstrate that hASCs do not constitutively express immunomodulatory factors. Conditioned supernatants from hASCs stimulated by IFN-gamma, PBMCs, or activated PBMCs highly inhibited PBMC proliferation, indicating that inhibitory factors are released upon hASC activation. Many factors have been involved in MSC-mediated immunosuppression, including IFN-gamma, IL-10, hepatocyte growth factor, prostaglandin E2, transforming growth factor-beta1, indoleamine 2,3-dioxygenase (IDO), nitric oxide, and IL-10. Using pharmacological inhibitors, neutralizing antibodies, and genetically modified hASCs that constitutively express or silence IDO enzyme, we demonstrate that, in the case of hASCs, the IFN-gamma/IDO axis is essential. Taken together, our data support the key role of IDO in the therapeutic use of hASC on immunomediated diseases.
DelaRosa
Olga
O
Cellerix S.A., Parque Tecnológico de Madrid, Tres Cantos, Madrid, Spain. orosa@cellerix.com
Lombardo
Eleuterio
E
Beraza
Aitor
A
Mancheño-Corvo
Pablo
P
Ramirez
Cristina
C
Menta
Ramón
R
Rico
Laura
L
Camarillo
Eva
E
García
Laura
L
Abad
José Luis
JL
Trigueros
Cesar
C
Delgado
Mario
M
Büscher
Dirk
D
D017667:Adipocytes / Q000166:cytology*; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology; D049109:Cell Proliferation; D015232:Dinoprostone / Q000378:metabolism; D005434:Flow Cytometry; D017228:Hepatocyte Growth Factor / Q000378:metabolism; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000378:metabolism*; D007371:Interferon-gamma / Q000378:metabolism*; D016753:Interleukin-10 / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000166:cytology; D008214:Lymphocytes / Q000166:cytology* / Q000276:immunology; D059630:Mesenchymal Stem Cells / Q000166:cytology*; D009569:Nitric Oxide / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D023822:Tissue Engineering; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D053773:Transforming Growth Factor beta1; D016753:Interleukin-10; D009569:Nitric Oxide; D017228:Hepatocyte Growth Factor; D007371:Interferon-gamma; D015232:Dinoprostone