Transient suppression of TGFβ receptor signaling facilitates human islet transplantation

Xiangwei Xiao, Shane Fischbach, Zewen Song, Iljana Gaffar, Ray Zimmerman, John Wiersch, Krishna Prasadan, Chiyo Shiota, Ping Guo, Sabarinathan Ramachandran, Piotr Witkowski, George K. Gittes

Research output: Contribution to journalArticlepeer-review

17 Scopus citations

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 immunedeficient 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.

Original languageEnglish (US)
Pages (from-to)1348-1356
Number of pages9
JournalEndocrinology
Volume157
Issue number4
DOIs
StatePublished - Apr 2016

Bibliographical note

Funding Information:
This work was supported by the National Institutes of Health Grant R01 DK098196 (to G.K.G.) and the Children's Hospital of Pittsburgh.

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