title: Mesenchymal Stem Cells Derived from Human Bone Marrow and Adipose Tissue Maintain Their Immunosuppressive Properties After Chondrogenic Differentiation: Role of HLA-G.
abstract: Mesenchymal stem cells (MSC) have emerged as alternative sources of stem cells for regenerative medicine because of their multipotency and strong immune-regulatory properties. Also, human leukocyte antigen G (HLA-G) is an important mediator of MSC-mediated immunomodulation. However, it is unclear whether MSC retain their immune-privileged potential after differentiation. As promising candidates for cartilage tissue engineering, the immunogenic and immunomodulatory properties of chondro-differentiated MSC (chondro-MSC) require in-depth exploration. In the present study, we used the alginate/hyaluronic acid (Alg/HA) hydrogel scaffold and induced both bone marrow- and adipose tissue-derived MSC into chondrocytes in three-dimensional condition. Then, MSC before and after chondrocyte differentiation were treated or not with interferon γ and tumor necrosis factor α mimicking inflammatory conditions and were compared side by side using flow cytometry, mixed lymphocyte reaction, and immunostaining assays. Results showed that chondro-MSC were hypoimmunogenic and could exert immunosuppression on HLA-mismatched peripheral blood mononuclear cells as well as undifferentiated MSC did. This alloproliferation inhibition mediated by MSC or chondro-MSC was dose dependent. Meanwhile, chondro-MSC exerted inhibition on natural killer cell-mediated cytolysis. Also, we showed that HLA-G expression was upregulated in chondro-MSC under hypoxia context and could be boosted in allogenic settings. Besides, the Alg/HA hydrogel scaffold was hypoimmunogenic and its addition for supporting MSC chondrocyte differentiation did not modify the immune properties of MSC. Finally, considering their chondro-regenerative potential and their retained immunosuppressive capacity, MSC constitute promising allogenic sources of stem cells for cartilage repair.
authors.affiliation: 1 CEA, Direction de la Recherche Fondamentale (DRF), Institut des Maladies Emergentes et des Therapies Innovantes (IMETI), Service de Recherche en Hemato-Immunologie (SRHI), Hopital Saint-Louis , IUH, Paris, France .|2 The State Key Laboratory of Experimental Hematology, Institute of Hematology and Hospital of Blood Disease , Chinese Academy of Medical Science, Peking Union Medical College, Tianjin, China .
authors.forename: Wen-Jing
authors.initials: WJ
authors.lastname: Du
authors.affiliation: 3 Cell and Tissue Banking Unit and Research Federation FR 3209, Nancy University Hospital , Nancy, France .|4 UMR CNRS 7365 and FR 3209 CNRS-INSERM-UL-CHU, Lorraine University , Vandoeuvre-Les-Nancy, France .|5 Microbiology-Immunology Department, Faculty of Pharmacy, Lorraine University , Nancy, France .
authors.forename: Loic
authors.initials: L
authors.lastname: Reppel
authors.affiliation: 3 Cell and Tissue Banking Unit and Research Federation FR 3209, Nancy University Hospital , Nancy, France .|4 UMR CNRS 7365 and FR 3209 CNRS-INSERM-UL-CHU, Lorraine University , Vandoeuvre-Les-Nancy, France .|5 Microbiology-Immunology Department, Faculty of Pharmacy, Lorraine University , Nancy, France .
authors.forename: Léonore
authors.initials: L
authors.lastname: Leger
authors.affiliation: 1 CEA, Direction de la Recherche Fondamentale (DRF), Institut des Maladies Emergentes et des Therapies Innovantes (IMETI), Service de Recherche en Hemato-Immunologie (SRHI), Hopital Saint-Louis , IUH, Paris, France .|6 Sorbonne Paris Cite, IUH, Hopital Saint-Louis, UMR_E5, Universite Paris Diderot , Paris, France .
authors.forename: Chantal
authors.initials: C
authors.lastname: Schenowitz
authors.affiliation: 4 UMR CNRS 7365 and FR 3209 CNRS-INSERM-UL-CHU, Lorraine University , Vandoeuvre-Les-Nancy, France .
authors.forename: Celine
authors.initials: C
authors.lastname: Huselstein
authors.affiliation: 3 Cell and Tissue Banking Unit and Research Federation FR 3209, Nancy University Hospital , Nancy, France .|4 UMR CNRS 7365 and FR 3209 CNRS-INSERM-UL-CHU, Lorraine University , Vandoeuvre-Les-Nancy, France .|5 Microbiology-Immunology Department, Faculty of Pharmacy, Lorraine University , Nancy, France .
authors.forename: Danièle
authors.initials: D
authors.lastname: Bensoussan
authors.affiliation: 1 CEA, Direction de la Recherche Fondamentale (DRF), Institut des Maladies Emergentes et des Therapies Innovantes (IMETI), Service de Recherche en Hemato-Immunologie (SRHI), Hopital Saint-Louis , IUH, Paris, France .|6 Sorbonne Paris Cite, IUH, Hopital Saint-Louis, UMR_E5, Universite Paris Diderot , Paris, France .
authors.forename: Edgardo D
authors.initials: ED
authors.lastname: Carosella
authors.affiliation: 2 The State Key Laboratory of Experimental Hematology, Institute of Hematology and Hospital of Blood Disease , Chinese Academy of Medical Science, Peking Union Medical College, Tianjin, China .
authors.forename: Zhong-Chao
authors.initials: ZC
authors.lastname: Han
authors.affiliation: 1 CEA, Direction de la Recherche Fondamentale (DRF), Institut des Maladies Emergentes et des Therapies Innovantes (IMETI), Service de Recherche en Hemato-Immunologie (SRHI), Hopital Saint-Louis , IUH, Paris, France .|6 Sorbonne Paris Cite, IUH, Hopital Saint-Louis, UMR_E5, Universite Paris Diderot , Paris, France .
authors.forename: Nathalie
authors.initials: N
authors.lastname: Rouas-Freiss
mesh_terms: D000273:Adipose Tissue / Q000166:cytology*; D000464:Alginates / Q000494:pharmacology; D000906:Antibodies / Q000494:pharmacology; D001854:Bone Marrow Cells / Q000166:cytology* / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D060833:Cellular Microenvironment / Q000187:drug effects; D019902:Chondrocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D020219:Chondrogenesis / Q000187:drug effects; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D020723:Glucuronic Acid / Q000494:pharmacology; D006684:HLA-DR Antigens / Q000378:metabolism; D059951:HLA-G Antigens / Q000378:metabolism*; D006603:Hexuronic Acids / Q000494:pharmacology; D006801:Humans; D006820:Hyaluronic Acid / Q000494:pharmacology; D007165:Immunosuppression Therapy; D007371:Interferon-gamma / Q000494:pharmacology; D007694:Killer Cells, Natural / Q000166:cytology / Q000187:drug effects; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000187:drug effects; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D000464:Alginates; D000906:Antibodies; D006684:HLA-DR Antigens; D059951:HLA-G Antigens; D006603:Hexuronic Acids; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D020723:Glucuronic Acid; D006820:Hyaluronic Acid