Transient Suppression of TGFß Receptor Signaling Facilitates Human Islet Transplantation.

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 TGFß receptor signaling in ß-cells has been shown to increase ß-cell proliferation in mice, but has not been rigorously examined in humans. Here, treatment of human islets with a TGFß receptor I inhibitor, SB-431542 (SB), significantly improved C-peptide secretion by ß-cells, and significantly increased ß-cell number by increasing ß-cell proliferation. In addition, SB increased cell-cycle activators and decreased cell-cycle suppressors in human ß-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 ß-cell proliferation in the graft, compared with controls. Thus, our data suggest that transient suppression of TGFß receptor signaling may improve the outcome of human islet transplantation, seemingly through increasing ß-cell number and function.