Human mesenchymal stem cells license adult CD34+ hemopoietic progenitor cells to differentiate into regulatory dendritic cells through activation of the Notch pathway.
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-beta, 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-beta. 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 gamma-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.
Li
Yin-Ping
YP
Laboratory of Mechanobiology and Engineering of Cells and Tissues, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 7563, Children's Hospital, Centre Hospitalier Université de Nancy, Vandoeuvre-lès-Nancy, France.
Paczesny
Sophie
S
Lauret
Evelyne
E
Poirault
Sonia
S
Bordigoni
Pierre
P
Mekhloufi
Fatiha
F
Hequet
Olivier
O
Bertrand
Yves
Y
Ou-Yang
Jing-Ping
JP
Stoltz
Jean-François
JF
Miossec
Pierre
P
Eljaafari
Assia
A
D000911:Antibodies, Monoclonal / Q000494:pharmacology; D018952:Antigens, CD34 / Q000032:analysis; D018106:CD28 Antigens / Q000276:immunology; D017252:CD3 Complex / Q000276:immunology; D002454:Cell Differentiation; D002478:Cells, Cultured; D018920:Coculture Techniques; D045142:Cross-Priming; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology*; D006412:Hematopoietic Stem Cells / Q000166:cytology*; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000166:cytology*; D051880:Receptors, Notch / Q000819:agonists*; D013601:T-Lymphocytes / Q000187:drug effects
D000911:Antibodies, Monoclonal; D018952:Antigens, CD34; D018106:CD28 Antigens; D017252:CD3 Complex; D051880:Receptors, Notch