A role for heme oxygenase-1 in the immunosuppressive effect of adult rat and human mesenchymal stem cells.
Mesenchymal stem cells (MSCs) display immunomodulatory properties mediated by various factors, including inducible nitric oxide synthase (iNOS). Since heme oxygenase-1 (HO-1) is a potent immunosuppressive enzyme, we tested the hypothesis that HO-1 could mediate the immunosuppressive effects of MSCs. We generated adult rat MSCs that inhibited T-cell proliferation in vitro. These MSCs expressed both HO-1 and iNOS. In vitro, whereas neither HO-1 nor iNOS inhibition alone could interfere with the immunosuppressive properties of rat MSCs, simultaneous inhibition of both enzymes restored T-cell proliferation. In vivo, injection of MSCs significantly delayed heart allograft rejection, and inhibition of either HO-1 or iNOS totally reversed the protective activity of MSCs, inducing rejection. Adult human MSCs also expressed HO-1; in these cells, HO-1 inhibition was sufficient to completely block their immunosuppressive capacity. In conclusion, we show, for the first time, that HO-1 mediates the immunosuppressive properties of rat and human MSCs.
Institut National de la Santé et de la Recherche Médicale (INSERM), U643, Nantes, France. dominiquechabannes@nantes.inserm.fr
Dominique
D
Chabannes
Marcelo
M
Hill
Emmanuel
E
Merieau
Julien
J
Rossignol
Régis
R
Brion
Jean Paul
JP
Soulillou
Ignacio
I
Anegon
Maria Cristina
MC
Cuturi
D000818:Animals; D002478:Cells, Cultured; D006085:Graft Survival; D016027:Heart Transplantation / Q000276:immunology; D051547:Heme Oxygenase-1 / Q000502:physiology*; D006801:Humans; D007108:Immune Tolerance / Q000235:genetics*; D059630:Mesenchymal Stem Cells / Q000187:drug effects / Q000276:immunology / Q000502:physiology*; D008665:Metalloporphyrins / Q000494:pharmacology; D011524:Protoporphyrins / Q000494:pharmacology; D051381:Rats; D023001:Transplantation Tolerance / Q000276:immunology; D016042:Transplantation, Heterotopic / Q000276:immunology
D008665:Metalloporphyrins; D011524:Protoporphyrins; C032628:tin protoporphyrin IX; D051547:Heme Oxygenase-1