Transplantation of pancreatic progenitors or insulin-secreting cells derived from human embryonic stem cells (hESCs) has been proposed as a therapy for diabetes. We describe a seven-stage protocol that efficiently converts hESCs into insulin-producing cells. Stage (S) 7 cells expressed key markers of mature pancreatic beta cells, including MAFA, and displayed glucose-stimulated insulin secretion similar to that of human islets during static incubations in vitro. Additional characterization using single-cell imaging and dynamic glucose stimulation assays revealed similarities but also notable differences between S7 insulin-secreting cells and primary human beta cells. Nevertheless, S7 cells rapidly reversed diabetes in mice within 40 days, roughly four times faster than pancreatic progenitors. Therefore, although S7 cells are not fully equivalent to mature beta cells, their capacity for glucose-responsive insulin secretion and rapid reversal of diabetes in vivo makes them a promising alternative to pancreatic progenitor cells or cadaveric islets for the treatment of diabetes.
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This work was supported in part by funding from the JDRF, the Canadian Institutes of Health Research (CIHR) Regenerative Medicine and Nanomedicine Initiative, and the Stem Cell Network (SCN). J.E.B. was funded by a JDRF postdoctoral fellowship and L'Oreal Canada for Women in Science Research Excellence Fellowship. Y.H.C.Y. was the recipient of an NSERC Post Graduate Scholarship and M.M. was the recipient of a Mitacs Elevate Postdoctoral Fellowship. The CIHR Transplantation Training Program provided funding for J.E.B., N.Q. and M.M. We also thank Stem Cell Technologies for their financial support, T. Webber, S. Karuna and B. Hu for their technical assistance, and G. Warnock and Z. Ao from the Irving K. Barber Human Islet Isolation Laboratory (Vancouver, BC) for providing human islets.
A. Rezania, P.A., A. Rubin and I.B. are employees of Janssen R&D, LLC; T.J.K. received financial support from Janssen R&D, LLC, for the research described in this article.
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Rezania, A., Bruin, J., Arora, P. et al. Reversal of diabetes with insulin-producing cells derived in vitro from human pluripotent stem cells. Nat Biotechnol 32, 1121–1133 (2014). https://doi.org/10.1038/nbt.3033
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