title: Mesenchymal stem cell and derived exosome as small RNA carrier and Immunomodulator to improve islet transplantation.
abstract: Human bone marrow mesenchymal stem cells (hBMSCs) and their exosomes can suppress immune reaction and deliver small RNAs. Thus, they may improve islet transplantation by delivering small RNAs for promoting islet function and inhibiting immune rejection. Here, we proposed an hBMSC and its exosome-based therapy to overcome immune rejection and poor islet function, both of which hinder the success of islet transplantation. We found overexpressed siFas and anti-miR-375 in plasmid encoding shFas and anti-miR-375 transfected hBMSC-derived exosomes, which silenced Fas and miR-375 of human islets and improved their viability and function against inflammatory cytokines. This plasmid transfected hBMSCs downregulated Fas and miR-375 of human islets in a humanized NOD scid gamma (NSG) mouse model, whose immune reaction was inhibited by injecting hBMSC and peripheral blood mononuclear cell (PBMC) co-cultured exosomes. These exosomes suppressed immune reaction by inhibiting PBMC proliferation and enhancing regulatory T cell (Treg) function. Collectively, our studies elucidated the mechanisms of RNA delivery from hBMSCs to human islets and the immunosuppressive effect of hBMSC and peripheral blood mononuclear cell co-cultured exosomes for improving islet transplantation.
authors.affiliation: Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE 68198, United States.
authors.forename: Di
authors.initials: D
authors.lastname: Wen
authors.affiliation: Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE 68198, United States.
authors.forename: Yang
authors.initials: Y
authors.lastname: Peng
authors.affiliation: Department of Chemistry, University of Chicago, Chicago, IL 60637, United States.
authors.forename: Di
authors.initials: D
authors.lastname: Liu
authors.affiliation: Department of Chemistry, University of Chicago, Chicago, IL 60637, United States.
authors.forename: Yossi
authors.initials: Y
authors.lastname: Weizmann
authors.affiliation: Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE 68198, United States. Electronic address: ram.mahato@unmc.edu.
authors.forename: Ram I
authors.initials: RI
authors.lastname: Mahato
mesh_terms: D000818:Animals; D000070416:Antagomirs / Q000008:administration & dosage* / Q000235:genetics / Q000627:therapeutic use; D002460:Cell Line; D055354:Exosomes / Q000235:genetics / Q000276:immunology / Q000637:transplantation*; D006084:Graft Rejection / Q000235:genetics / Q000276:immunology; D006801:Humans; D007165:Immunosuppression Therapy / Q000379:methods*; D007515:Islets of Langerhans / Q000276:immunology* / Q000378:metabolism; D016381:Islets of Langerhans Transplantation / Q000379:methods*; D059630:Mesenchymal Stem Cells / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D035683:MicroRNAs / Q000235:genetics; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000235:genetics / Q000627:therapeutic use; D000067492:RNAi Therapeutics / Q000379:methods; D051381:Rats; D019014:fas Receptor / Q000235:genetics / Q000276:immunology
chemical_list: D000070416:Antagomirs; C540933:MIRN375 microRNA, human; D035683:MicroRNAs; D034741:RNA, Small Interfering; D019014:fas Receptor
keywords: Exosome; Immunotherapy; Islet transplantation; Type 1 diabetes