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* Laboratory of Mechanobiology and Engineering of Cells and Tissues, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 7563, and Faculty of Medicine, Unit of Cellular and Tissue Therapy, and
Hematology Department, Children’s Hospital, Centre Hospitalier Université de Nancy, Vandoeuvre-lès-Nancy, France;
Department of Pathology and Pathophysiology, Wuhan University, Wuhan, China;
Department of Pediatrics, University of Michigan Comprehensive Cancer Center, Ann Arbor, MI 48109;
¶ Cell Therapy Unit, Etablissement Francais du Sang, Rhône-Alpes, France;
|| Département d’Hématologie Pédiatrique, Hôpital Debrousse, Lyon, France;
# Institut National de la Santé et de la Recherche Médicale Unité 790, and Institut Gustave Roussy, Villejuif, France, and Université Paris-Sud 11, Orsay, France; and
** Immunogenomics Unit, Equipe d’Accueil 4061, Hôpital Edouard Herriot, Lyon, France and Université Claude Bernard Lyon I, Villeurbanne, France
The mechanisms underlying the immunomodulatory functions of mesenchymal stem cells (MSC) on dendritic cells (DC) have been shown to involve soluble factors, such as IL-6 or TGF-β, or cell-cell contact, or both depending on the report referenced. In this study, we intend to clarify these mechanisms by examining the immunosuppressive effect of human adult MSC on adult DC differentiated from CD34+ hemopoietic progenitor cells (HPC). MSC have been shown to inhibit interstitial DC differentiation from monocytes and umbilical CD34+ HPC. In this study, we confirm that MSC not only halt interstitial DC but also Langerhans cell differentiation from adult CD34+ HPC, as assessed by the decreased expression of CD1a, CD14, CD86, CD80, and CD83 Ags on their cell surface. Accordingly, the functional capacity of CD34+ HPC-derived DC (CD34-DC) to stimulate alloreactive T cells was impaired. Furthermore, we showed that 1) MSC inhibited commitment of CD34+ HPC into immature DC, but not maturation of CD34-DC, 2) this inhibitory effect was reversible, and 3) DC generated in coculture with MSC (MSC-DC) induced the generation of alloantigen-specific regulatory T cells following secondary allostimulation. Conditioned medium from MSC cultures showed some inhibitory effect independent of IL-6, M-CSF, and TGF-β. In comparison, direct coculture of MSC with CD34+ HPC resulted in much stronger immunosuppressive effect and led to an activation of the Notch pathway as assessed by the overexpression of Hes1 in MSC-DC. Finally, DAPT, a 
-secretase inhibitor that inhibits Notch signaling, was able to overcome MSC-DC defects. In conclusion, our data suggest that MSC license adult CD34+ HPC to differentiate into regulatory DC through activation of the Notch pathway.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported in part by la Ligue Nationale contre le Cancer Meurthe et Moselle. Y.-P.L. is a recipient of French foreign government department fellowship.
2 Y.-P.L. and S.P. contributed equally to this work.
3 Address correspondence and reprint requests to Dr. Sophie Paczesny, Department of Pediatrics, 6420 Cancer and Geriatrics Center, University of Michigan Comprehensive Cancer Center, 1500 East Medical Center Drive, Ann Arbor, MI 48109-0942. E-mail address: sophiep{at}umich.edu
4 Abbreviations used in this paper: MSC, mesenchymal stem cell; DC, dendritic cell; HPC, hemopoietic progenitor cell; MNC, mononuclear cell; CD34-DC, CD34+ HPC-derived DC; MSC-DC, DC generated in coculture with MSC.
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