title: MiR-375 promotes redifferentiation of adult human β cells expanded in vitro.
abstract: In-vitro expansion of β cells from adult human pancreatic islets could provide abundant cells for cell replacement therapy of diabetes. However, proliferation of β-cell-derived (BCD) cells is associated with dedifferentiation. Here we analyzed changes in microRNAs (miRNAs) during BCD cell dedifferentiation and identified miR-375 as one of the miRNAs greatly downregulated. We hypothesized that restoration of miR-375 expression in expanded BCD cells may contribute to their redifferentiation. Our findings demonstrate that overexpression of miR-375 alone leads to activation of β-cell gene expression, reduced cell proliferation, and a switch from N-cadherin to E-cadherin expression, which characterizes mesenchymal-epithelial transition. These effects, which are reproducible in cells derived from multiple human donors, are likely mediated by repression of PDPK1 transcripts and indirect downregulation of GSK3 activity. These findings support an important role of miR-375 in regulation of human β-cell phenotype, and suggest that miR-375 upregulation may facilitate the generation of functional insulin-producing cells following ex-vivo expansion of human islet cells.
authors: Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors: Gili
authors: G
authors: Nathan
authors: Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.
authors: Sharon
authors: S
authors: Kredo-Russo
authors: Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors: Tamar
authors: T
authors: Geiger
authors: Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors: Ayelet
authors: A
authors: Lenz
authors: Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.
authors: Haggai
authors: H
authors: Kaspi
authors: Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.
authors: Eran
authors: E
authors: Hornstein
authors: Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors: Shimon
authors: S
authors: Efrat
mesh_terms: D064413:3-Phosphoinositide-Dependent Protein Kinases / Q000096:biosynthesis; D000328:Adult; D015820:Cadherins / Q000096:biosynthesis; D002454:Cell Differentiation / Q000235:genetics*; D049109:Cell Proliferation / Q000235:genetics; D064987:Cell- and Tissue-Based Therapy; D003920:Diabetes Mellitus / Q000235:genetics* / Q000628:therapy; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D066298:In Vitro Techniques; D007328:Insulin / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000378:metabolism* / Q000637:transplantation; D007515:Islets of Langerhans / Q000166:cytology / Q000378:metabolism; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism
chemical_list: D015820:Cadherins; D007328:Insulin; C540933:MIRN375 microRNA, human; D035683:MicroRNAs; D064413:3-Phosphoinositide-Dependent Protein Kinases; C578562:PDPK1 protein, human