title: Identification of miRNAs Involved in Reprogramming Acinar Cells into Insulin Producing Cells.
abstract: Reprogramming acinar cells into insulin producing cells using adenoviral (Ad)-mediated delivery of Pdx1, Ngn3 and MafA (PNM) is an innovative approach for the treatment of diabetes. Here, we aimed to investigate the molecular mechanisms involved in this process and in particular, the role of microRNAs. To this end, we performed a comparative study of acinar-to-β cell reprogramming efficiency in the rat acinar cell line AR42J and its subclone B13 after transduction with Ad-PNM. B13 cells were more efficiently reprogrammed than AR42J cells, which was demonstrated by a strong activation of β cell markers (Ins1, Ins2, IAPP, NeuroD1 and Pax4). miRNome panels were used to analyze differentially expressed miRNAs in acinar cells under four experimental conditions (i) non-transduced AR42J cells, (ii) non-transduced B13 cells, (iii) B13 cells transduced with Ad-GFP vectors and (iv) B13 cells transduced with Ad-PNM vectors. A total of 59 miRNAs were found to be differentially expressed between non-transduced AR42J and B13 cells. Specifically, the miR-200 family was completely repressed in B13 cells, suggesting that these cells exist in a less differentiated state than AR42J cells and as a consequence they present a greater plasticity. Adenoviral transduction per se induced dedifferentiation of acinar cells and 11 miRNAs were putatively involved in this process, whereas 8 miRNAs were found to be associated with PNM expression. Of note, Ad-PNM reprogrammed B13 cells presented the same levels of miR-137-3p, miR-135a-5p, miR-204-5p and miR-210-3p of those detected in islets, highlighting their role in the process. In conclusion, this study led to the identification of miRNAs that might be of compelling importance to improve acinar-to-β cell conversion for the future treatment of diabetes.
authors.affiliation: Center of Animal Biotechnology and Gene Therapy, Universitat Autònoma de Barcelona, Bellaterra, Spain.|Department of Biochemistry and Molecular Biology, School of Veterinary Medicine. Universitat Autònoma de Barcelona, Bellaterra, Spain.
authors.forename: Joan
authors.initials: J
authors.lastname: Teichenne
authors.affiliation: Center of Animal Biotechnology and Gene Therapy, Universitat Autònoma de Barcelona, Bellaterra, Spain.|Department of Biochemistry and Molecular Biology, School of Veterinary Medicine. Universitat Autònoma de Barcelona, Bellaterra, Spain.|CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid, Spain.
authors.forename: Meritxell
authors.initials: M
authors.lastname: Morró
authors.affiliation: Center of Animal Biotechnology and Gene Therapy, Universitat Autònoma de Barcelona, Bellaterra, Spain.|Department of Biochemistry and Molecular Biology, School of Veterinary Medicine. Universitat Autònoma de Barcelona, Bellaterra, Spain.|CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid, Spain.
authors.forename: Alba
authors.initials: A
authors.lastname: Casellas
authors.affiliation: Center of Animal Biotechnology and Gene Therapy, Universitat Autònoma de Barcelona, Bellaterra, Spain.|Department of Biochemistry and Molecular Biology, School of Veterinary Medicine. Universitat Autònoma de Barcelona, Bellaterra, Spain.|CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid, Spain.
authors.forename: Veronica
authors.initials: V
authors.lastname: Jimenez
authors.affiliation: CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid, Spain.|Bellvitge Biomedical Research Institute, IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain.
authors.forename: Noelia
authors.initials: N
authors.lastname: Tellez
authors.affiliation: Laboratoire de Thérapie Génique, INSERM UMR1089, University of Nantes and Atlantic Gene Therapies, Nantes, France.
authors.forename: Adrien
authors.initials: A
authors.lastname: Leger
authors.affiliation: Center of Animal Biotechnology and Gene Therapy, Universitat Autònoma de Barcelona, Bellaterra, Spain.|Department of Biochemistry and Molecular Biology, School of Veterinary Medicine. Universitat Autònoma de Barcelona, Bellaterra, Spain.|CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid, Spain.
authors.forename: Fatima
authors.initials: F
authors.lastname: Bosch
authors.affiliation: Center of Animal Biotechnology and Gene Therapy, Universitat Autònoma de Barcelona, Bellaterra, Spain.|Department of Biochemistry and Molecular Biology, School of Veterinary Medicine. Universitat Autònoma de Barcelona, Bellaterra, Spain.|CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid, Spain.|Laboratoire de Thérapie Génique, INSERM UMR1089, University of Nantes and Atlantic Gene Therapies, Nantes, France.
authors.forename: Eduard
authors.initials: E
authors.lastname: Ayuso
mesh_terms: D061354:Acinar Cells / Q000166:cytology / Q000378:metabolism*; D000256:Adenoviridae; D000818:Animals; D000943:Antigens, Differentiation / Q000096:biosynthesis / Q000235:genetics; D002460:Cell Line; D000067470:Cellular Reprogramming Techniques; D007328:Insulin / Q000235:genetics / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000378:metabolism*; D051381:Rats; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics; D014161:Transduction, Genetic
chemical_list: D000943:Antigens, Differentiation; D007328:Insulin; D014157:Transcription Factors