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      Generation of stem cell-derived β-cells from patients with type 1 diabetes.

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          Abstract

          We recently reported the scalable in vitro production of functional stem cell-derived β-cells (SC-β cells). Here we extend this approach to generate the first SC-β cells from type 1 diabetic patients (T1D). β-cells are destroyed during T1D disease progression, making it difficult to extensively study them in the past. These T1D SC-β cells express β-cell markers, respond to glucose both in vitro and in vivo, prevent alloxan-induced diabetes in mice and respond to anti-diabetic drugs. Furthermore, we use an in vitro disease model to demonstrate the cells respond to different forms of β-cell stress. Using these assays, we find no major differences in T1D SC-β cells compared with SC-β cells derived from non-diabetic patients. These results show that T1D SC-β cells could potentially be used for the treatment of diabetes, drug screening and the study of β-cell biology.

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          Generation of functional human pancreatic β cells in vitro.

          Felicia W Pagliuca, Jeffrey Millman, Mads Gürtler … (2014)
          The generation of insulin-producing pancreatic β cells from stem cells in vitro would provide an unprecedented cell source for drug discovery and cell transplantation therapy in diabetes. However, insulin-producing cells previously generated from human pluripotent stem cells (hPSC) lack many functional characteristics of bona fide β cells. Here, we report a scalable differentiation protocol that can generate hundreds of millions of glucose-responsive β cells from hPSC in vitro. These stem-cell-derived β cells (SC-β) express markers found in mature β cells, flux Ca(2+) in response to glucose, package insulin into secretory granules, and secrete quantities of insulin comparable to adult β cells in response to multiple sequential glucose challenges in vitro. Furthermore, these cells secrete human insulin into the serum of mice shortly after transplantation in a glucose-regulated manner, and transplantation of these cells ameliorates hyperglycemia in diabetic mice. Copyright © 2014 Elsevier Inc. All rights reserved.
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            Reversal of diabetes with insulin-producing cells derived in vitro from human pluripotent stem cells.

            Alireza Rezania, Jennifer Bruin, Payal Arora … (2014)
            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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              Pancreatic endoderm derived from human embryonic stem cells generates glucose-responsive insulin-secreting cells in vivo.

              Evert Kroon, Laura Martinson, Kuniko Kadoya … (2008)
              Development of a cell therapy for diabetes would be greatly aided by a renewable supply of human beta-cells. Here we show that pancreatic endoderm derived from human embryonic stem (hES) cells efficiently generates glucose-responsive endocrine cells after implantation into mice. Upon glucose stimulation of the implanted mice, human insulin and C-peptide are detected in sera at levels similar to those of mice transplanted with approximately 3,000 human islets. Moreover, the insulin-expressing cells generated after engraftment exhibit many properties of functional beta-cells, including expression of critical beta-cell transcription factors, appropriate processing of proinsulin and the presence of mature endocrine secretory granules. Finally, in a test of therapeutic potential, we demonstrate that implantation of hES cell-derived pancreatic endoderm protects against streptozotocin-induced hyperglycemia. Together, these data provide definitive evidence that hES cells are competent to generate glucose-responsive, insulin-secreting cells.
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                Author and article information

                Journal
                Journal ID (iso-abbrev): Nat Commun
                Title: Nature communications
                Publisher: Springer Nature
                ISSN (Electronic): 2041-1723
                ISSN (Print): 2041-1723
                Publication date (Electronic): May 10 2016
                Volume: 7
                Affiliations
                [1 ] Division of Endocrinology, Metabolism and Lipid Research, Washington University School of Medicine, Campus Box 8127, 660 South Euclid Avenue, St Louis, Missouri 63110, USA.
                [2 ] Department of Biomedical Engineering, Washington University in St Louis, 1 Brookings Drive, St Louis, Missouri 63130, USA.
                [3 ] Department of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Harvard University 7 Divinity Avenue, Cambridge, Massachusetts 02138, USA.
                [4 ] Case Western Reserve University School of Medicine, 2109 Adelbert Road, Cleveland, Ohio 44106, USA.
                [5 ] Semma Therapeutics, Inc. 450 Kendall Street, Suite 2B Cambridge, Massachusetts 02142, USA.
                Article
                Publisher Item ID: ncomms11463
                DOI: 10.1038/ncomms11463
                PMC ID: 4866045
                PubMed ID: 27163171
                SO-VID: 373a9c23-8e99-41c1-8367-3c90ec7788db
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