title: Transient Suppression of TGFβ Receptor Signaling Facilitates Human Islet Transplantation.
abstract: Although islet transplantation is an effective treatment for severe diabetes, its broad application is greatly limited due to a shortage of donor islets. Suppression of TGFβ receptor signaling in β-cells has been shown to increase β-cell proliferation in mice, but has not been rigorously examined in humans. Here, treatment of human islets with a TGFβ receptor I inhibitor, SB-431542 (SB), significantly improved C-peptide secretion by β-cells, and significantly increased β-cell number by increasing β-cell proliferation. In addition, SB increased cell-cycle activators and decreased cell-cycle suppressors in human β-cells. Transplantation of SB-treated human islets into diabetic immune-deficient mice resulted in significant improvement in blood glucose control, significantly higher serum and graft insulin content, and significantly greater increases in β-cell proliferation in the graft, compared with controls. Thus, our data suggest that transient suppression of TGFβ receptor signaling may improve the outcome of human islet transplantation, seemingly through increasing β-cell number and function.
authors.affiliation: Division of Pediatric Surgery (X.X., S.F., Z.S., I.G., R.Z., J.W., K.P., C.S., P.G., G.K.G.), Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15224; Department of General Surgery (Z.S.), The Third Xiangya Hospital of Central S University, Changsha 410013, China; and Department of Surgery (S.R., P.W.), University of Chicago, Chicago, Illinois 60637.
authors.forename: Xiangwei
authors.initials: X
authors.lastname: Xiao
authors.affiliation: Division of Pediatric Surgery (X.X., S.F., Z.S., I.G., R.Z., J.W., K.P., C.S., P.G., G.K.G.), Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15224; Department of General Surgery (Z.S.), The Third Xiangya Hospital of Central S University, Changsha 410013, China; and Department of Surgery (S.R., P.W.), University of Chicago, Chicago, Illinois 60637.
authors.forename: Shane
authors.initials: S
authors.lastname: Fischbach
authors.affiliation: Division of Pediatric Surgery (X.X., S.F., Z.S., I.G., R.Z., J.W., K.P., C.S., P.G., G.K.G.), Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15224; Department of General Surgery (Z.S.), The Third Xiangya Hospital of Central S University, Changsha 410013, China; and Department of Surgery (S.R., P.W.), University of Chicago, Chicago, Illinois 60637.
authors.forename: Zewen
authors.initials: Z
authors.lastname: Song
authors.affiliation: Division of Pediatric Surgery (X.X., S.F., Z.S., I.G., R.Z., J.W., K.P., C.S., P.G., G.K.G.), Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15224; Department of General Surgery (Z.S.), The Third Xiangya Hospital of Central S University, Changsha 410013, China; and Department of Surgery (S.R., P.W.), University of Chicago, Chicago, Illinois 60637.
authors.forename: Iljana
authors.initials: I
authors.lastname: Gaffar
authors.affiliation: Division of Pediatric Surgery (X.X., S.F., Z.S., I.G., R.Z., J.W., K.P., C.S., P.G., G.K.G.), Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15224; Department of General Surgery (Z.S.), The Third Xiangya Hospital of Central S University, Changsha 410013, China; and Department of Surgery (S.R., P.W.), University of Chicago, Chicago, Illinois 60637.
authors.forename: Ray
authors.initials: R
authors.lastname: Zimmerman
authors.affiliation: Division of Pediatric Surgery (X.X., S.F., Z.S., I.G., R.Z., J.W., K.P., C.S., P.G., G.K.G.), Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15224; Department of General Surgery (Z.S.), The Third Xiangya Hospital of Central S University, Changsha 410013, China; and Department of Surgery (S.R., P.W.), University of Chicago, Chicago, Illinois 60637.
authors.forename: John
authors.initials: J
authors.lastname: Wiersch
authors.affiliation: Division of Pediatric Surgery (X.X., S.F., Z.S., I.G., R.Z., J.W., K.P., C.S., P.G., G.K.G.), Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15224; Department of General Surgery (Z.S.), The Third Xiangya Hospital of Central S University, Changsha 410013, China; and Department of Surgery (S.R., P.W.), University of Chicago, Chicago, Illinois 60637.
authors.forename: Krishna
authors.initials: K
authors.lastname: Prasadan
authors.affiliation: Division of Pediatric Surgery (X.X., S.F., Z.S., I.G., R.Z., J.W., K.P., C.S., P.G., G.K.G.), Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15224; Department of General Surgery (Z.S.), The Third Xiangya Hospital of Central S University, Changsha 410013, China; and Department of Surgery (S.R., P.W.), University of Chicago, Chicago, Illinois 60637.
authors.forename: Chiyo
authors.initials: C
authors.lastname: Shiota
authors.affiliation: Division of Pediatric Surgery (X.X., S.F., Z.S., I.G., R.Z., J.W., K.P., C.S., P.G., G.K.G.), Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15224; Department of General Surgery (Z.S.), The Third Xiangya Hospital of Central S University, Changsha 410013, China; and Department of Surgery (S.R., P.W.), University of Chicago, Chicago, Illinois 60637.
authors.forename: Ping
authors.initials: P
authors.lastname: Guo
authors.affiliation: Division of Pediatric Surgery (X.X., S.F., Z.S., I.G., R.Z., J.W., K.P., C.S., P.G., G.K.G.), Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15224; Department of General Surgery (Z.S.), The Third Xiangya Hospital of Central S University, Changsha 410013, China; and Department of Surgery (S.R., P.W.), University of Chicago, Chicago, Illinois 60637.
authors.forename: Sabarinathan
authors.initials: S
authors.lastname: Ramachandran
authors.affiliation: Division of Pediatric Surgery (X.X., S.F., Z.S., I.G., R.Z., J.W., K.P., C.S., P.G., G.K.G.), Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15224; Department of General Surgery (Z.S.), The Third Xiangya Hospital of Central S University, Changsha 410013, China; and Department of Surgery (S.R., P.W.), University of Chicago, Chicago, Illinois 60637.
authors.forename: Piotr
authors.initials: P
authors.lastname: Witkowski
authors.affiliation: Division of Pediatric Surgery (X.X., S.F., Z.S., I.G., R.Z., J.W., K.P., C.S., P.G., G.K.G.), Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15224; Department of General Surgery (Z.S.), The Third Xiangya Hospital of Central S University, Changsha 410013, China; and Department of Surgery (S.R., P.W.), University of Chicago, Chicago, Illinois 60637.
authors.forename: George K
authors.initials: GK
authors.lastname: Gittes
mesh_terms: D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D001786:Blood Glucose / Q000378:metabolism; D015153:Blotting, Western; D002096:C-Peptide / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004149:Dioxoles / Q000494:pharmacology; D005260:Female; D006801:Humans; D007328:Insulin / Q000097:blood / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism*; D016381:Islets of Langerhans Transplantation / Q000379:methods*; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D018613:Microscopy, Confocal; 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 / Q000502:physiology*; D014183:Transplantation, Heterologous
chemical_list: C459179:4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide; D001549:Benzamides; D001786:Blood Glucose; D002096:C-Peptide; D004149:Dioxoles; D007328:Insulin; D018125:Receptors, Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I