title: Identification and Characterization of microRNAs Associated With Human β-Cell Loss in a Mouse Model.
abstract: Currently there is no effective approach for monitoring early β-cell loss during islet graft rejection following human islet transplantation (HIT). Due to ethical and technical constraints, it is difficult to directly study biomarkers of islet destruction in humans. Here, we established a humanized mouse model with induced human β-cell death using adoptive lymphocyte transfer (ALT). Human islet grafts of ALT-treated mice had perigraft lymphocyte infiltration, fewer insulin+β cells, and increased β-cell apoptosis. Islet-specific miR-375 was used to validate our model, and expression of miR-375 was significantly decreased in the grafts and increased in the circulation of ALT-treated mice before hyperglycemia. A NanoString expression assay was further used to profile 800 human miRNAs in the human islet grafts, and the results were validated using quantitative real-time polymerase chain reaction. We found that miR-4454 and miR-199a-5p were decreased in the human islet grafts following ALT and increased in the circulation prior to hyperglycemia. These data demonstrate that our in vivo model of induced human β-cell destruction is a robust method for identifying and characterizing circulating biomarkers, and suggest that miR-4454 and miR-199a-5p can serve as novel biomarkers associated with early human β-cell loss following HIT.
authors.affiliation: The Sanford Project, Sanford Research, Sioux Falls, SD.
authors.forename: R
authors.initials: R
authors.lastname: Roat
authors.affiliation: The Sanford Project, Sanford Research, Sioux Falls, SD.
authors.forename: M M
authors.initials: MM
authors.lastname: Hossain
authors.affiliation: The Sanford Project, Sanford Research, Sioux Falls, SD.
authors.forename: J
authors.initials: J
authors.lastname: Christopherson
authors.affiliation: The Sanford Project, Sanford Research, Sioux Falls, SD.
authors.forename: C
authors.initials: C
authors.lastname: Free
authors.affiliation: The Sanford Project, Sanford Research, Sioux Falls, SD.
authors.forename: S
authors.initials: S
authors.lastname: Jain
authors.affiliation: Department of Fundamental Neurosciences, University of Lausanne, Lausanne, Switzerland.
authors.forename: C
authors.initials: C
authors.lastname: Guay
authors.affiliation: Department of Fundamental Neurosciences, University of Lausanne, Lausanne, Switzerland.
authors.forename: R
authors.initials: R
authors.lastname: Regazzi
authors.affiliation: The Sanford Project, Sanford Research, Sioux Falls, SD.|Department of Pediatrics and Surgery, University of South Dakota, Sioux Falls, SD.
authors.forename: Z
authors.initials: Z
authors.lastname: Guo
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D017209:Apoptosis; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000235:genetics* / Q000628:therapy; D004195:Disease Models, Animal; D005260:Female; D006085:Graft Survival; D006801:Humans; D006943:Hyperglycemia / Q000209:etiology; D050417:Insulin-Secreting Cells / Q000378:metabolism / Q000473:pathology*; D016381:Islets of Langerhans Transplantation; D008214:Lymphocytes / Q000276:immunology / Q000473:pathology; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D035683:MicroRNAs / Q000235:genetics*
chemical_list: D035683:MicroRNAs
keywords: basic (laboratory) research/science; cell death; diabetes: type 1; endocrinology/diabetology; islet transplantation; islets of Langerhans; molecular biology; molecular biology: microRNA