TY - JOUR
T1 - Transient suppression of TGFβ receptor signaling facilitates human islet transplantation
AU - Xiao, Xiangwei
AU - Fischbach, Shane
AU - Song, Zewen
AU - Gaffar, Iljana
AU - Zimmerman, Ray
AU - Wiersch, John
AU - Prasadan, Krishna
AU - Shiota, Chiyo
AU - Guo, Ping
AU - Ramachandran, Sabarinathan
AU - Witkowski, Piotr
AU - Gittes, George K.
N1 - Publisher Copyright:
Copyright © 2016 by the Endocrine Society.
PY - 2016/4
Y1 - 2016/4
N2 - 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.
AB - 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.
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U2 - 10.1210/en.2015-1986
DO - 10.1210/en.2015-1986
M3 - Article
C2 - 26872091
AN - SCOPUS:84964412501
SN - 0013-7227
VL - 157
SP - 1348
EP - 1356
JO - Endocrinology
JF - Endocrinology
IS - 4
ER -