title: Inhibition of TGF-β Signaling Promotes Human Pancreatic β-Cell Replication.
abstract: Diabetes is associated with loss of functional pancreatic β-cells, and restoration of β-cells is a major goal for regenerative therapies. Endogenous regeneration of β-cells via β-cell replication has the potential to restore cellular mass; however, pharmacological agents that promote regeneration or expansion of endogenous β-cells have been elusive. The regenerative capacity of β-cells declines rapidly with age, due to accumulation of p16(INK4a), resulting in limited capacity for adult endocrine pancreas regeneration. Here, we show that transforming growth factor-β (TGF-β) signaling via Smad3 integrates with the trithorax complex to activate and maintain Ink4a expression to prevent β-cell replication. Importantly, inhibition of TGF-β signaling can result in repression of the Ink4a/Arf locus, resulting in increased β-cell replication in adult mice. Furthermore, small molecule inhibitors of the TGF-β pathway promote β-cell replication in human islets transplanted into NOD-scid IL-2Rg(null) mice. These data reveal a novel role for TGF-β signaling in the regulation of the Ink4a/Arf locus and highlight the potential of using small molecule inhibitors of TGF-β signaling to promote human β-cell replication.
authors.affiliation: Division of Endocrinology, Department of Medicine, University of California, Los Angeles, Los Angeles, CA.
authors.forename: Sangeeta
authors.initials: S
authors.lastname: Dhawan
authors.affiliation: Islet Cell and Regenerative Biology, Joslin Diabetes Center and Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
authors.forename: Ercument
authors.initials: E
authors.lastname: Dirice
authors.affiliation: Islet Cell and Regenerative Biology, Joslin Diabetes Center and Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
authors.forename: Rohit N
authors.initials: RN
authors.lastname: Kulkarni
authors.affiliation: Diabetes Center, University of California, San Francisco, San Francisco, CA anil.bhushan@ucsf.edu.
authors.forename: Anil
authors.initials: A
authors.lastname: Bhushan
mesh_terms: D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000819:agonists / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D004149:Dioxoles / Q000494:pharmacology; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D016381:Islets of Langerhans Transplantation / Q000502:physiology; D008297:Male; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008822:Mice, Transgenic; D018125:Receptors, Transforming Growth Factor beta / Q000819:agonists / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012038:Regeneration / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects*; D051900:Smad3 Protein / Q000378:metabolism*; D014015:Tissue Banks; D053773:Transforming Growth Factor beta1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014183:Transplantation, Heterologous; D016042:Transplantation, Heterotopic
chemical_list: C459179:4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide; D001549:Benzamides; C000614131:CDKN2A protein, human; D019941:Cyclin-Dependent Kinase Inhibitor p16; D004149:Dioxoles; D007328:Insulin; D018125:Receptors, Transforming Growth Factor beta; C497790:SMAD3 protein, human; D051900:Smad3 Protein; C508960:TGFB1 protein, human; D053773:Transforming Growth Factor beta1