title: Stromal Cells Act as Guardians for Endothelial Progenitors by Reducing Their Immunogenicity After Co-Transplantation.
abstract: Regeneration of injured tissues requires effective therapeutic strategies supporting vasculogenesis. The lack of instantly available autologous cell sources and immunogenicity of allogeneic endothelial (progenitor) cells limits clinical progress. Based on the immunosuppressive potency of mesenchymal stem/progenitor cells (MSCs), we investigated whether crosstalk between endothelial colony-forming progenitor cells (ECFCs) and MSCs during vasculogenesis could lower allogeneic T cell responses against ECFCs allowing long-term engraftment in vivo. Immunodeficient mice received subcutaneous grafts containing human ECFCs alone, or pairs of human ECFCs/MSCs from the same umbilical cord (UC) to study vasculogenesis in the presence of human leukocyte antigen (HLA)-mismatched human peripheral blood mononuclear cells (PBMCs). In vitro, cell surface marker changes due to interferon gamma (IFNγ) stimulation during ECFC/MSC coculture were determined and further effects on allostimulated T cell proliferation and cytotoxic lysis were measured. IFNγ-induced HLA-DR expression on ECFCs and MSCs, but both cell types had significantly less HLA-DR in cocultures. ECFC-induced T cell proliferation was abolished after MSC coculture as a result of HLA-DR downregulation and indolamin-2,3-dioxygenase activation. Additionally, allospecific CD8+T cell-mediated lysis of ECFCs was reduced in cocultures. ECFC/MSC coapplication in immunodeficient mice not only promoted the generation of improved blood vessel architecture after 6 weeks, but also reduced intragraft immune cell infiltration and endothelial HLA-DR expression following PBMC reconstitution. Crosstalk between UC-derived ECFCs and MSCs after combined transplantation can lower the risk of ECFC rejection, thus enabling their coapplication for therapeutic vasculogenesis. Stem Cells 2017;35:1233-1245.
authors.affiliation: Institute of Medical Immunology, Charité Universitätsmedizin Berlin, Campus Virchow-Klinikum, Berlin, Germany.|Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Charité Universitätsmedizin Berlin, Campus Virchow-Klinikum, Berlin, Germany.
authors.forename: Naima
authors.initials: N
authors.lastname: Souidi
authors.affiliation: Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Charité Universitätsmedizin Berlin, Campus Virchow-Klinikum, Berlin, Germany.
authors.forename: Meaghan
authors.initials: M
authors.lastname: Stolk
authors.affiliation: Institute of Medical Immunology, Charité Universitätsmedizin Berlin, Campus Virchow-Klinikum, Berlin, Germany.
authors.forename: Juliane
authors.initials: J
authors.lastname: Rudeck
authors.affiliation: Institute of Experimental and Clinical Cell Therapy, Paracelsus Medical University, Salzburg, Austria.|Spinal Cord & Tissue Regeneration Center, Paracelsus Medical University, Salzburg, Austria.
authors.forename: Dirk
authors.initials: D
authors.lastname: Strunk
authors.affiliation: Spinal Cord & Tissue Regeneration Center, Paracelsus Medical University, Salzburg, Austria.|Department for Blood Group Serology and Transfusion Medicine, Paracelsus Medical University, Salzburg, Austria.
authors.forename: Katharina
authors.initials: K
authors.lastname: Schallmoser
authors.affiliation: Institute of Medical Immunology, Charité Universitätsmedizin Berlin, Campus Virchow-Klinikum, Berlin, Germany.|Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Charité Universitätsmedizin Berlin, Campus Virchow-Klinikum, Berlin, Germany.
authors.forename: Hans-Dieter
authors.initials: HD
authors.lastname: Volk
authors.affiliation: Institute of Medical Immunology, Charité Universitätsmedizin Berlin, Campus Virchow-Klinikum, Berlin, Germany.|Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Charité Universitätsmedizin Berlin, Campus Virchow-Klinikum, Berlin, Germany.
authors.forename: Martina
authors.initials: M
authors.lastname: Seifert
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D018920:Coculture Techniques; D003114:Colony-Forming Units Assay; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology* / Q000637:transplantation*; D005260:Female; D006684:HLA-DR Antigens / Q000378:metabolism; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000378:metabolism; D007249:Inflammation / Q000473:pathology; D007371:Interferon-gamma / Q000494:pharmacology; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology*; D051379:Mice; D018919:Neovascularization, Physiologic / Q000187:drug effects; D017154:Stromal Cells / Q000166:cytology / Q000187:drug effects / Q000637:transplantation
chemical_list: D006684:HLA-DR Antigens; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D007371:Interferon-gamma
keywords: Cell transplantation; Endothelial progenitor cells; Histocompatibility antigens; Immunomodulation; Neovascularization; Stromal cells