title: Exploiting Expression of Hippo Effector, Yap, for Expansion of Functional Islet Mass.
abstract: Loss of pancreas β-cell function is the precipitating factor in all forms of diabetes. Cell replacement therapies, such as islet transplantation, remain the best hope for a cure; however, widespread implementation of this method is hampered by availability of donor tissue. Thus, strategies that expand functional β-cell mass are crucial for widespread usage in diabetes cell replacement therapy. Here, we investigate the regulation of the Hippo-target protein, Yes-associated protein (Yap), during development of the endocrine pancreas and its function after reactivation in human cadaveric islets. Our results demonstrate that Yap expression is extinguished at the mRNA level after neurogenin-3-dependent specification of the pancreas endocrine lineage, correlating with proliferation decreases in these cells. Interestingly, when a constitutively active form of Yap was expressed in human cadaver islets robust increases in proliferation were noted within insulin-producing β-cells. Importantly, proliferation in these cells occurs without negatively affecting β-cell differentiation or functional status. Finally, we show that the proproliferative mammalian target of rapamycin pathway is activated after Yap expression, providing at least one explanation for the observed increases in β-cell proliferation. Together, these results provide a foundation for manipulating Yap activity as a novel approach to expand functional islet mass for diabetes regenerative therapy.
authors.affiliation: Holland Regenerative Medicine Program (N.M.G., B.P.B., S.U.R.M., Z.G., N.E.S.), University of Nebraska Medical Center, Omaha, Nebraska 68198; Department of Surgery (N.M.G., S.U.R.M., Z.G., N.E.S.), University of Nebraska Medical Center, Omaha 68198, Nebraska; and Department of Internal Medicine (B.P.B.), University of Nebraska Medical Center, Omaha, Nebraska 68198.
authors.forename: Nicholas M
authors.initials: NM
authors.lastname: George
authors.affiliation: Holland Regenerative Medicine Program (N.M.G., B.P.B., S.U.R.M., Z.G., N.E.S.), University of Nebraska Medical Center, Omaha, Nebraska 68198; Department of Surgery (N.M.G., S.U.R.M., Z.G., N.E.S.), University of Nebraska Medical Center, Omaha 68198, Nebraska; and Department of Internal Medicine (B.P.B.), University of Nebraska Medical Center, Omaha, Nebraska 68198.
authors.forename: Brian P
authors.initials: BP
authors.lastname: Boerner
authors.affiliation: Holland Regenerative Medicine Program (N.M.G., B.P.B., S.U.R.M., Z.G., N.E.S.), University of Nebraska Medical Center, Omaha, Nebraska 68198; Department of Surgery (N.M.G., S.U.R.M., Z.G., N.E.S.), University of Nebraska Medical Center, Omaha 68198, Nebraska; and Department of Internal Medicine (B.P.B.), University of Nebraska Medical Center, Omaha, Nebraska 68198.
authors.forename: Shakeel U R
authors.initials: SU
authors.lastname: Mir
authors.affiliation: Holland Regenerative Medicine Program (N.M.G., B.P.B., S.U.R.M., Z.G., N.E.S.), University of Nebraska Medical Center, Omaha, Nebraska 68198; Department of Surgery (N.M.G., S.U.R.M., Z.G., N.E.S.), University of Nebraska Medical Center, Omaha 68198, Nebraska; and Department of Internal Medicine (B.P.B.), University of Nebraska Medical Center, Omaha, Nebraska 68198.
authors.forename: Zachary
authors.initials: Z
authors.lastname: Guinn
authors.affiliation: Holland Regenerative Medicine Program (N.M.G., B.P.B., S.U.R.M., Z.G., N.E.S.), University of Nebraska Medical Center, Omaha, Nebraska 68198; Department of Surgery (N.M.G., S.U.R.M., Z.G., N.E.S.), University of Nebraska Medical Center, Omaha 68198, Nebraska; and Department of Internal Medicine (B.P.B.), University of Nebraska Medical Center, Omaha, Nebraska 68198.
authors.forename: Nora E
authors.initials: NE
authors.lastname: Sarvetnick
mesh_terms: D000217:Acyltransferases; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000096:biosynthesis / Q000235:genetics; D018797:Cell Cycle Proteins; D002454:Cell Differentiation; D002460:Cell Line; D049109:Cell Proliferation; D003920:Diabetes Mellitus / Q000235:genetics* / Q000473:pathology; D018507:Gene Expression Regulation, Developmental / Q000235:genetics*; D000090683:Hippo Signaling Pathway; D006801:Humans; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins; D007515:Islets of Langerhans / Q000166:cytology / Q000196:embryology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000235:genetics; D010750:Phosphoproteins / Q000235:genetics*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D000090742:Serine-Threonine Kinase 3; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics; D000091102:YAP-Signaling Proteins; D000099317:Hippo Kinases
chemical_list: D000217:Acyltransferases; D048868:Adaptor Proteins, Signal Transducing; D051792:Basic Helix-Loop-Helix Proteins; D018797:Cell Cycle Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; D010750:Phosphoproteins; D017346:Protein Serine-Threonine Kinases; D012333:RNA, Messenger; D000090742:Serine-Threonine Kinase 3; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; C407737:Neurog3 protein, mouse; C486223:Yap1 protein, mouse; C486363:tafazzin protein, mouse; C095566:STK4 protein, human; D000099317:Hippo Kinases; C097835:STK3 protein, human