title: Reversal of β cell de-differentiation by a small molecule inhibitor of the TGFβ pathway.
abstract: Dysfunction or death of pancreatic β cells underlies both types of diabetes. This functional decline begins with β cell stress and de-differentiation. Current drugs for type 2 diabetes (T2D) lower blood glucose levels but they do not directly alleviate β cell stress nor prevent, let alone reverse, β cell de-differentiation. We show here that Urocortin 3 (Ucn3), a marker for mature β cells, is down-regulated in the early stages of T2D in mice and when β cells are stressed in vitro. Using an insulin expression-coupled lineage tracer, with Ucn3 as a reporter for the mature β cell state, we screen for factors that reverse β cell de-differentiation. We find that a small molecule inhibitor of TGFβ receptor I (Alk5) protects cells from the loss of key β cell transcription factors and restores a mature β cell identity even after exposure to prolonged and severe diabetes.
authors.affiliation: Department of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Harvard University, Cambridge, United States.
authors.forename: Barak
authors.initials: B
authors.lastname: Blum
authors.affiliation: Department of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Harvard University, Cambridge, United States.
authors.forename: Adam N
authors.initials: AN
authors.lastname: Roose
authors.affiliation: Department of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Harvard University, Cambridge, United States.
authors.forename: Ornella
authors.initials: O
authors.lastname: Barrandon
authors.affiliation: Department of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Harvard University, Cambridge, United States.
authors.forename: René
authors.initials: R
authors.lastname: Maehr
authors.affiliation: Department of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Harvard University, Cambridge, United States.
authors.forename: Anthony C
authors.initials: AC
authors.lastname: Arvanites
authors.affiliation: Department of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Harvard University, Cambridge, United States.
authors.forename: Lance S
authors.initials: LS
authors.lastname: Davidow
authors.affiliation: Department of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Harvard University, Cambridge, United States.
authors.forename: Jeffrey C
authors.initials: JC
authors.lastname: Davis
authors.affiliation: Department of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Harvard University, Cambridge, United States.
authors.forename: Quinn P
authors.initials: QP
authors.lastname: Peterson
authors.affiliation: Department of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Harvard University, Cambridge, United States.
authors.forename: Lee L
authors.initials: LL
authors.lastname: Rubin
authors.affiliation: Department of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Harvard University, Cambridge, United States.
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Melton
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D054337:Cell Dedifferentiation / Q000187:drug effects*; D016207:Cytokines / Q000494:pharmacology; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007333:Insulin Resistance; D050417:Insulin-Secreting Cells / Q000473:pathology*; D008810:Mice, Inbred C57BL; D009419:Nerve Tissue Proteins / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D054852:Small Molecule Libraries / Q000494:pharmacology*; D013312:Stress, Physiological / Q000187:drug effects; D014157:Transcription Factors / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects; D054832:Urocortins / Q000378:metabolism
chemical_list: C116599:Artn protein, mouse; D015415:Biomarkers; D016207:Cytokines; D009419:Nerve Tissue Proteins; D018125:Receptors, Transforming Growth Factor beta; D054852:Small Molecule Libraries; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D054832:Urocortins; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; C000625841:TGFBR1 protein, human; C000625842:Tgfbr1 protein, mouse
keywords: Alk5 inhibitor II; Tgf-beta; Ucn3; beta cells; cell biology; dedifferentiation; developmental biology; diabetes; human; mouse; stem cells