Immunomodulation of endothelial differentiated mesenchymal stromal cells: impact on T and NK cells.
Wharton's jelly mesenchymal stromal cells (WJ-MSCs) are promising candidates for tissue engineering, as their immunomodulatory activity allows them to escape immune recognition and to suppress several immune cell functions. To date, however, few studies have investigated the effect of differentiation of the MSCs on this immunomodulation. To address this question, we sought to determine the impact of differentiation toward endothelial cells on immunoregulation by WJ-MSCs. Following differentiation, the endothelial-like cells (ELCs) were positive for CD31, vascular endothelial cadherin and vascular endothelial growth factor receptor 2, and able to take up acetylated low-density lipoproteins. The expression of HLA-DR and CD86, which contribute to MSCs immunoprivilege, was still weak after differentiation. We then co-cultured un- and differentiated MSCs with immune cells, under conditions of both direct and indirect contact. The proliferation and phenotype of the immune cells were analyzed and the mediators secreted by both ELCs and WJ-MSCs quantified. Interleukin (IL)-6, IL-1β, prostaglandin E2 and in particular indoleamine-2,3-dioxygenase expression were upregulated in ELCs on stimulation by T and NK cells, suggesting the possible involvement of these factors in allosuppression. ELCs co-cultured with T cells were able to generate CD25(+) T cells, which were shown to be of the CD4(+)CD25(+)FoxP3(+) regulatory subset. Direct contact between NK cells and ELCs or WJ-MSCs decreased the level of NK-activating receptor natural-killer group 2, member D. Moreover, direct co-culturing with ELCs stimulates CD73 acquisition on NK cells, a mechanism which may induce adenosine secretion by the cells and lead to an immunosuppressive function. Taken together, our results show that ELCs obtained following differentiation of WJ-MSCs remain largely immunosuppressive.
Université de Lorraine, UMR CNRS 7365, Ingénierie moléculaire et physiopathologie articulaire (IMoPa), Batiment Biopole, Faculté de Médecine, Vandoeuvre-Les-Nancy, France.|Fédération de Recherche 3209, CNRS-INSERM-Université de Lorraine-CHU, Nancy, France.
Reine
R
El Omar
Université de Lorraine, UMR CNRS 7365, Ingénierie moléculaire et physiopathologie articulaire (IMoPa), Batiment Biopole, Faculté de Médecine, Vandoeuvre-Les-Nancy, France.|Fédération de Recherche 3209, CNRS-INSERM-Université de Lorraine-CHU, Nancy, France.|CHU de Nancy, Unité de Thérapie Cellulaire et banque de Tissus, allée du Morvan, Vandoeuvre-Les-Nancy, France.
Yu
Y
Xiong
Université de Lorraine, UMR CNRS 7365, Ingénierie moléculaire et physiopathologie articulaire (IMoPa), Batiment Biopole, Faculté de Médecine, Vandoeuvre-Les-Nancy, France.|Fédération de Recherche 3209, CNRS-INSERM-Université de Lorraine-CHU, Nancy, France.
Gabriel
G
Dostert
Fédération de Recherche 3209, CNRS-INSERM-Université de Lorraine-CHU, Nancy, France.|Institut National de la Santé et de la Recherche Médicale (INSERM) U1116, Faculté de Médecine, Vandoeuvre-Les-Nancy, France.
Huguette
H
Louis
Université de Lorraine, UMR CNRS 7365, Ingénierie moléculaire et physiopathologie articulaire (IMoPa), Batiment Biopole, Faculté de Médecine, Vandoeuvre-Les-Nancy, France.|Fédération de Recherche 3209, CNRS-INSERM-Université de Lorraine-CHU, Nancy, France.
Monique
M
Gentils
Université de Lorraine, UMR CNRS 7365, Ingénierie moléculaire et physiopathologie articulaire (IMoPa), Batiment Biopole, Faculté de Médecine, Vandoeuvre-Les-Nancy, France.|Fédération de Recherche 3209, CNRS-INSERM-Université de Lorraine-CHU, Nancy, France.
Patrick
P
Menu
Université de Lorraine, UMR CNRS 7365, Ingénierie moléculaire et physiopathologie articulaire (IMoPa), Batiment Biopole, Faculté de Médecine, Vandoeuvre-Les-Nancy, France.|Fédération de Recherche 3209, CNRS-INSERM-Université de Lorraine-CHU, Nancy, France.|CHU de Nancy, Unité de Thérapie Cellulaire et banque de Tissus, allée du Morvan, Vandoeuvre-Les-Nancy, France.
Jean-François
JF
Stoltz
Université de Lorraine, UMR CNRS 7365, Ingénierie moléculaire et physiopathologie articulaire (IMoPa), Batiment Biopole, Faculté de Médecine, Vandoeuvre-Les-Nancy, France.|Fédération de Recherche 3209, CNRS-INSERM-Université de Lorraine-CHU, Nancy, France.
Émilie
É
Velot
Université de Lorraine, UMR CNRS 7365, Ingénierie moléculaire et physiopathologie articulaire (IMoPa), Batiment Biopole, Faculté de Médecine, Vandoeuvre-Les-Nancy, France.|Fédération de Recherche 3209, CNRS-INSERM-Université de Lorraine-CHU, Nancy, France.|CHU de Nancy, Unité de Thérapie Cellulaire et banque de Tissus, allée du Morvan, Vandoeuvre-Les-Nancy, France.
Véronique
V
Decot
D015720:5'-Nucleotidase / Q000378:metabolism; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D018920:Coculture Techniques; D016207:Cytokines / Q000378:metabolism; D042783:Endothelial Cells / Q000502:physiology*; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006801:Humans; D007165:Immunosuppression Therapy; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000235:genetics / Q000378:metabolism; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D007694:Killer Cells, Natural / Q000502:physiology*; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000502:physiology*; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000502:physiology*
D016207:Cytokines; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D053645:Interleukin-2 Receptor alpha Subunit; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D015720:5'-Nucleotidase