Skip to main content
Top
Published in: Diabetologia 10/2016

01-10-2016 | Review

The quest to make fully functional human pancreatic beta cells from embryonic stem cells: climbing a mountain in the clouds

Author: James D. Johnson

Published in: Diabetologia | Issue 10/2016

Login to get access

Abstract

The production of fully functional insulin-secreting cells to treat diabetes is a major goal of regenerative medicine. In this article, I review progress towards this goal over the last 15 years from the perspective of a beta cell biologist. I describe the current state-of-the-art, and speculate on the general approaches that will be required to identify and achieve our ultimate goal of producing functional beta cells. The need for deeper phenotyping of heterogeneous cultures of stem cell derived islet-like cells in parallel with a better understanding of the heterogeneity of the target cell type(s) is emphasised. This deep phenotyping should include high-throughput single-cell analysis, as well as comprehensive ’omics technologies to provide unbiased characterisation of cell products and human beta cells. There are justified calls for more detailed and well-powered studies of primary human pancreatic beta cell physiology, and I propose online databases of standardised human beta cell responses to physiological stimuli, including both functional and metabolomic/proteomic/transcriptomic profiles. With a concerted, community-wide effort, including both basic and applied scientists, beta cell replacement will become a clinical reality for patients with diabetes.
Appendix
Available only for authorised users
Literature
1.
go back to reference Ryan EA, Paty BW, Senior PA et al (2005) Five-year follow-up after clinical islet transplantation. Diabetes 54:2060–2069CrossRefPubMed Ryan EA, Paty BW, Senior PA et al (2005) Five-year follow-up after clinical islet transplantation. Diabetes 54:2060–2069CrossRefPubMed
2.
go back to reference Thompson DM, Meloche M, Ao Z et al (2011) Reduced progression of diabetic microvascular complications with islet cell transplantation compared with intensive medical therapy. Transplantation 91:373–378CrossRefPubMed Thompson DM, Meloche M, Ao Z et al (2011) Reduced progression of diabetic microvascular complications with islet cell transplantation compared with intensive medical therapy. Transplantation 91:373–378CrossRefPubMed
3.
go back to reference Bruin JE, Rezania A, Kieffer TJ (2015) Replacing and safeguarding pancreatic β cells for diabetes. Sci Transl Med 7:316ps323CrossRef Bruin JE, Rezania A, Kieffer TJ (2015) Replacing and safeguarding pancreatic β cells for diabetes. Sci Transl Med 7:316ps323CrossRef
4.
go back to reference Misler S, Barnett DW, Gillis KD, Pressel DM (1992) Electrophysiology of stimulus-secretion coupling in human β-cells. Diabetes 41:1221–1228CrossRefPubMed Misler S, Barnett DW, Gillis KD, Pressel DM (1992) Electrophysiology of stimulus-secretion coupling in human β-cells. Diabetes 41:1221–1228CrossRefPubMed
5.
go back to reference Keenan HA, Sun JK, Levine J et al (2010) Residual insulin production and pancreatic β-cell turnover after 50 years of diabetes: Joslin Medalist Study. Diabetes 59:2846–2853CrossRefPubMedPubMedCentral Keenan HA, Sun JK, Levine J et al (2010) Residual insulin production and pancreatic β-cell turnover after 50 years of diabetes: Joslin Medalist Study. Diabetes 59:2846–2853CrossRefPubMedPubMedCentral
6.
go back to reference Smukler SR, Arntfield ME, Razavi R et al (2011) The adult mouse and human pancreas contain rare multipotent stem cells that express insulin. Cell Stem Cell 8:281–293CrossRefPubMed Smukler SR, Arntfield ME, Razavi R et al (2011) The adult mouse and human pancreas contain rare multipotent stem cells that express insulin. Cell Stem Cell 8:281–293CrossRefPubMed
7.
go back to reference Chera S, Baronnier D, Ghila L et al (2014) Diabetes recovery by age-dependent conversion of pancreatic δ-cells into insulin producers. Nature 514:503–507CrossRefPubMedPubMedCentral Chera S, Baronnier D, Ghila L et al (2014) Diabetes recovery by age-dependent conversion of pancreatic δ-cells into insulin producers. Nature 514:503–507CrossRefPubMedPubMedCentral
8.
10.
go back to reference Kushner JA, MacDonald PE, Atkinson MA (2014) Stem cells to insulin secreting cells: two steps forward and now a time to pause? Cell Stem Cell 15:535–536CrossRefPubMed Kushner JA, MacDonald PE, Atkinson MA (2014) Stem cells to insulin secreting cells: two steps forward and now a time to pause? Cell Stem Cell 15:535–536CrossRefPubMed
12.
go back to reference Bartlett ST, Markmann JF, Johnson P et al (2016) Report from IPITA-TTS opinion leaders meeting on the future of β-cell replacement. Transplantation 100(Suppl 2):S1–S44CrossRefPubMedPubMedCentral Bartlett ST, Markmann JF, Johnson P et al (2016) Report from IPITA-TTS opinion leaders meeting on the future of β-cell replacement. Transplantation 100(Suppl 2):S1–S44CrossRefPubMedPubMedCentral
13.
go back to reference Dominguez-Bendala J, Lanzoni G, Klein D, Alvarez-Cubela S, Pastori RL (2016) The human endocrine pancreas: new insights on replacement and regeneration. Trends Endocrinol Metab 27:153–162CrossRefPubMed Dominguez-Bendala J, Lanzoni G, Klein D, Alvarez-Cubela S, Pastori RL (2016) The human endocrine pancreas: new insights on replacement and regeneration. Trends Endocrinol Metab 27:153–162CrossRefPubMed
14.
go back to reference Quiskamp N, Bruin JE, Kieffer TJ (2015) Differentiation of human pluripotent stem cells into β-cells: potential and challenges. Best Pract Res Clin Endocrinol Metab 29:833–847CrossRefPubMed Quiskamp N, Bruin JE, Kieffer TJ (2015) Differentiation of human pluripotent stem cells into β-cells: potential and challenges. Best Pract Res Clin Endocrinol Metab 29:833–847CrossRefPubMed
16.
go back to reference Leon-Quinto T, Jones J, Skoudy A, Burcin M, Soria B (2004) In vitro directed differentiation of mouse embryonic stem cells into insulin-producing cells. Diabetologia 47:1442–1451CrossRefPubMed Leon-Quinto T, Jones J, Skoudy A, Burcin M, Soria B (2004) In vitro directed differentiation of mouse embryonic stem cells into insulin-producing cells. Diabetologia 47:1442–1451CrossRefPubMed
17.
18.
go back to reference Lumelsky N, Blondel O, Laeng P, Velasco I, Ravin R, McKay R (2001) Differentiation of embryonic stem cells to insulin-secreting structures similar to pancreatic islets. Science 292:1389–1394CrossRefPubMed Lumelsky N, Blondel O, Laeng P, Velasco I, Ravin R, McKay R (2001) Differentiation of embryonic stem cells to insulin-secreting structures similar to pancreatic islets. Science 292:1389–1394CrossRefPubMed
19.
go back to reference Shiroi A, Yoshikawa M, Yokota H et al (2002) Identification of insulin-producing cells derived from embryonic stem cells by zinc-chelating dithizone. Stem Cells 20:284–292CrossRefPubMed Shiroi A, Yoshikawa M, Yokota H et al (2002) Identification of insulin-producing cells derived from embryonic stem cells by zinc-chelating dithizone. Stem Cells 20:284–292CrossRefPubMed
20.
go back to reference Soria B, Roche E, Berna G, Leon-Quinto T, Reig JA, Martin F (2000) Insulin-secreting cells derived from embryonic stem cells normalize glycemia in streptozotocin-induced diabetic mice. Diabetes 49:157–162CrossRefPubMed Soria B, Roche E, Berna G, Leon-Quinto T, Reig JA, Martin F (2000) Insulin-secreting cells derived from embryonic stem cells normalize glycemia in streptozotocin-induced diabetic mice. Diabetes 49:157–162CrossRefPubMed
21.
go back to reference Hori Y, Rulifson IC, Tsai BC, Heit JJ, Cahoy JD, Kim SK (2002) Growth inhibitors promote differentiation of insulin-producing tissue from embryonic stem cells. Proc Natl Acad Sci U S A 99:16105–16110CrossRefPubMedPubMedCentral Hori Y, Rulifson IC, Tsai BC, Heit JJ, Cahoy JD, Kim SK (2002) Growth inhibitors promote differentiation of insulin-producing tissue from embryonic stem cells. Proc Natl Acad Sci U S A 99:16105–16110CrossRefPubMedPubMedCentral
22.
go back to reference Assady S, Maor G, Amit M, Itskovitz-Eldor J, Skorecki KL, Tzukerman M (2001) Insulin production by human embryonic stem cells. Diabetes 50:1691–1697CrossRefPubMed Assady S, Maor G, Amit M, Itskovitz-Eldor J, Skorecki KL, Tzukerman M (2001) Insulin production by human embryonic stem cells. Diabetes 50:1691–1697CrossRefPubMed
23.
go back to reference Treutelaar MK, Skidmore JM, Dias-Leme CL et al (2003) Nestin-lineage cells contribute to the microvasculature but not endocrine cells of the islet. Diabetes 52:2503–2512CrossRefPubMed Treutelaar MK, Skidmore JM, Dias-Leme CL et al (2003) Nestin-lineage cells contribute to the microvasculature but not endocrine cells of the islet. Diabetes 52:2503–2512CrossRefPubMed
24.
go back to reference Sipione S, Eshpeter A, Lyon JG, Korbutt GS, Bleackley RC (2004) Insulin expressing cells from differentiated embryonic stem cells are not beta cells. Diabetologia 47:499–508CrossRefPubMed Sipione S, Eshpeter A, Lyon JG, Korbutt GS, Bleackley RC (2004) Insulin expressing cells from differentiated embryonic stem cells are not beta cells. Diabetologia 47:499–508CrossRefPubMed
25.
go back to reference Mehran AE, Templeman NM, Brigidi GS et al (2012) Hyperinsulinemia drives diet-induced obesity independently of brain insulin production. Cell Metab 16:723–737CrossRefPubMed Mehran AE, Templeman NM, Brigidi GS et al (2012) Hyperinsulinemia drives diet-induced obesity independently of brain insulin production. Cell Metab 16:723–737CrossRefPubMed
26.
go back to reference McKiernan E, Barron NW, O’Sullivan F, Barham P, Clynes M, O’Driscoll L (2007) Detecting de novo insulin synthesis in embryonic stem cell-derived populations. Exp Cell Res 313:1405–1414CrossRef McKiernan E, Barron NW, O’Sullivan F, Barham P, Clynes M, O’Driscoll L (2007) Detecting de novo insulin synthesis in embryonic stem cell-derived populations. Exp Cell Res 313:1405–1414CrossRef
27.
go back to reference Hansson M, Tonning A, Frandsen U et al (2004) Artifactual insulin release from differentiated embryonic stem cells. Diabetes 53:2603–2609CrossRefPubMed Hansson M, Tonning A, Frandsen U et al (2004) Artifactual insulin release from differentiated embryonic stem cells. Diabetes 53:2603–2609CrossRefPubMed
28.
go back to reference Micallef SJ, Janes ME, Knezevic K, Davis RP, Elefanty AG, Stanley EG (2005) Retinoic acid induces Pdx1-positive endoderm in differentiating mouse embryonic stem cells. Diabetes 54:301–305CrossRefPubMed Micallef SJ, Janes ME, Knezevic K, Davis RP, Elefanty AG, Stanley EG (2005) Retinoic acid induces Pdx1-positive endoderm in differentiating mouse embryonic stem cells. Diabetes 54:301–305CrossRefPubMed
29.
go back to reference D’Amour KA, Agulnick AD, Eliazer S, Kelly OG, Kroon E, Baetge EE (2005) Efficient differentiation of human embryonic stem cells to definitive endoderm. Nat Biotechnol 23:1534–1541CrossRefPubMed D’Amour KA, Agulnick AD, Eliazer S, Kelly OG, Kroon E, Baetge EE (2005) Efficient differentiation of human embryonic stem cells to definitive endoderm. Nat Biotechnol 23:1534–1541CrossRefPubMed
30.
go back to reference D’Amour KA, Bang AG, Eliazer S et al (2006) Production of pancreatic hormone-expressing endocrine cells from human embryonic stem cells. Nat Biotechnol 24:1392–1401CrossRefPubMed D’Amour KA, Bang AG, Eliazer S et al (2006) Production of pancreatic hormone-expressing endocrine cells from human embryonic stem cells. Nat Biotechnol 24:1392–1401CrossRefPubMed
31.
go back to reference Hrvatin S, O’Donnell CW, Deng F et al (2014) Differentiated human stem cells resemble fetal, not adult, β cells. Proc Natl Acad Sci U S A 111:3038–3043CrossRefPubMedPubMedCentral Hrvatin S, O’Donnell CW, Deng F et al (2014) Differentiated human stem cells resemble fetal, not adult, β cells. Proc Natl Acad Sci U S A 111:3038–3043CrossRefPubMedPubMedCentral
32.
go back to reference Basford CL, Prentice KJ, Hardy AB et al (2012) The functional and molecular characterisation of human embryonic stem cell-derived insulin-positive cells compared with adult pancreatic beta cells. Diabetologia 55:358–371CrossRefPubMed Basford CL, Prentice KJ, Hardy AB et al (2012) The functional and molecular characterisation of human embryonic stem cell-derived insulin-positive cells compared with adult pancreatic beta cells. Diabetologia 55:358–371CrossRefPubMed
33.
go back to reference Takeuchi H, Nakatsuji N, Suemori H (2014) Endodermal differentiation of human pluripotent stem cells to insulin-producing cells in 3D culture. Sci Rep 4:4488PubMedPubMedCentral Takeuchi H, Nakatsuji N, Suemori H (2014) Endodermal differentiation of human pluripotent stem cells to insulin-producing cells in 3D culture. Sci Rep 4:4488PubMedPubMedCentral
34.
go back to reference Nostro MC, Sarangi F, Ogawa S et al (2011) Stage-specific signaling through TGFβ family members and WNT regulates patterning and pancreatic specification of human pluripotent stem cells. Development 138:861–871CrossRefPubMedPubMedCentral Nostro MC, Sarangi F, Ogawa S et al (2011) Stage-specific signaling through TGFβ family members and WNT regulates patterning and pancreatic specification of human pluripotent stem cells. Development 138:861–871CrossRefPubMedPubMedCentral
35.
go back to reference Bruin JE, Erener S, Vela J et al (2014) Characterization of polyhormonal insulin-producing cells derived in vitro from human embryonic stem cells. Stem Cell Res 12:194–208CrossRefPubMed Bruin JE, Erener S, Vela J et al (2014) Characterization of polyhormonal insulin-producing cells derived in vitro from human embryonic stem cells. Stem Cell Res 12:194–208CrossRefPubMed
36.
go back to reference Kroon E, Martinson LA, Kadoya K et al (2008) Pancreatic endoderm derived from human embryonic stem cells generates glucose-responsive insulin-secreting cells in vivo. Nat Biotechnol 26:443–452CrossRefPubMed Kroon E, Martinson LA, Kadoya K et al (2008) Pancreatic endoderm derived from human embryonic stem cells generates glucose-responsive insulin-secreting cells in vivo. Nat Biotechnol 26:443–452CrossRefPubMed
37.
go back to reference Motte E, Szepessy E, Suenens K et al (2014) Composition and function of macroencapsulated human embryonic stem cell-derived implants: comparison with clinical human islet cell grafts. Am J Physiol Endocrinol Metab 307:E838–E846CrossRefPubMed Motte E, Szepessy E, Suenens K et al (2014) Composition and function of macroencapsulated human embryonic stem cell-derived implants: comparison with clinical human islet cell grafts. Am J Physiol Endocrinol Metab 307:E838–E846CrossRefPubMed
38.
go back to reference Bruin JE, Rezania A, Xu J et al (2013) Maturation and function of human embryonic stem cell-derived pancreatic progenitors in macroencapsulation devices following transplant into mice. Diabetologia 56:1987–1998CrossRefPubMed Bruin JE, Rezania A, Xu J et al (2013) Maturation and function of human embryonic stem cell-derived pancreatic progenitors in macroencapsulation devices following transplant into mice. Diabetologia 56:1987–1998CrossRefPubMed
39.
go back to reference Bruin JE, Asadi A, Fox JK, Erener S, Rezania A, Kieffer TJ (2015) Accelerated maturation of human stem cell-derived pancreatic progenitor cells into insulin-secreting cells in immunodeficient rats relative to mice. Stem Cell Rep 5:1081–1096CrossRef Bruin JE, Asadi A, Fox JK, Erener S, Rezania A, Kieffer TJ (2015) Accelerated maturation of human stem cell-derived pancreatic progenitor cells into insulin-secreting cells in immunodeficient rats relative to mice. Stem Cell Rep 5:1081–1096CrossRef
40.
go back to reference Rezania A, Bruin JE, Arora P et al (2014) Reversal of diabetes with insulin-producing cells derived in vitro from human pluripotent stem cells. Nat Biotechnol 32:1121–1133CrossRefPubMed Rezania A, Bruin JE, Arora P et al (2014) Reversal of diabetes with insulin-producing cells derived in vitro from human pluripotent stem cells. Nat Biotechnol 32:1121–1133CrossRefPubMed
41.
43.
go back to reference Vegas AJ, Veiseh O, Gürtler M et al (2016) Long-term glycemic control using polymer-encapsulated human stem cell-derived beta cells in immune-competent mice. Nat Med 22:306–311CrossRefPubMedPubMedCentral Vegas AJ, Veiseh O, Gürtler M et al (2016) Long-term glycemic control using polymer-encapsulated human stem cell-derived beta cells in immune-competent mice. Nat Med 22:306–311CrossRefPubMedPubMedCentral
44.
go back to reference Russ HA, Parent AV, Ringler JJ et al (2015) Controlled induction of human pancreatic progenitors produces functional beta-like cells in vitro. EMBO J 34:1759–1772CrossRefPubMedPubMedCentral Russ HA, Parent AV, Ringler JJ et al (2015) Controlled induction of human pancreatic progenitors produces functional beta-like cells in vitro. EMBO J 34:1759–1772CrossRefPubMedPubMedCentral
45.
46.
go back to reference Scharfmann R, Pechberty S, Hazhouz Y et al (2014) Development of a conditionally immortalized human pancreatic β cell line. J Clin Invest 124:2087–2098CrossRefPubMedPubMedCentral Scharfmann R, Pechberty S, Hazhouz Y et al (2014) Development of a conditionally immortalized human pancreatic β cell line. J Clin Invest 124:2087–2098CrossRefPubMedPubMedCentral
47.
go back to reference Korsgren E, Korsgren O (2016) Glucose effectiveness: the mouse trap in the development of novel β-cell replacement therapies. Transplantation 100:111–115CrossRefPubMed Korsgren E, Korsgren O (2016) Glucose effectiveness: the mouse trap in the development of novel β-cell replacement therapies. Transplantation 100:111–115CrossRefPubMed
48.
go back to reference Rutter GA, Pullen TJ, Hodson DJ, Martinez-Sanchez A (2015) Pancreatic β-cell identity, glucose sensing and the control of insulin secretion. Biochem J 466:203–218CrossRefPubMed Rutter GA, Pullen TJ, Hodson DJ, Martinez-Sanchez A (2015) Pancreatic β-cell identity, glucose sensing and the control of insulin secretion. Biochem J 466:203–218CrossRefPubMed
49.
go back to reference Lyon J, Manning Fox JE, Spigelman AF et al (2016) Research-focused isolation of human islets from donors with and without diabetes at the Alberta Diabetes Institute IsletCore. Endocrinology 157:560–569CrossRefPubMed Lyon J, Manning Fox JE, Spigelman AF et al (2016) Research-focused isolation of human islets from donors with and without diabetes at the Alberta Diabetes Institute IsletCore. Endocrinology 157:560–569CrossRefPubMed
50.
go back to reference Street CN, Lakey JR, Shapiro AM et al (2004) Islet graft assessment in the Edmonton Protocol: implications for predicting long-term clinical outcome. Diabetes 53:3107–3114CrossRefPubMed Street CN, Lakey JR, Shapiro AM et al (2004) Islet graft assessment in the Edmonton Protocol: implications for predicting long-term clinical outcome. Diabetes 53:3107–3114CrossRefPubMed
51.
go back to reference van de Bunt M, Manning Fox JE, Dai X et al (2015) Transcript expression data from human islets links regulatory signals from genome-wide association studies for type 2 diabetes and glycemic traits to their downstream effectors. PLoS Genet 11:e1005694CrossRefPubMedPubMedCentral van de Bunt M, Manning Fox JE, Dai X et al (2015) Transcript expression data from human islets links regulatory signals from genome-wide association studies for type 2 diabetes and glycemic traits to their downstream effectors. PLoS Genet 11:e1005694CrossRefPubMedPubMedCentral
52.
go back to reference Yang YH, Szabat M, Bragagnini C et al (2011) Paracrine signalling loops in adult human and mouse pancreatic islets: netrins modulate beta cell apoptosis signalling via dependence receptors. Diabetologia 54:828–842CrossRefPubMed Yang YH, Szabat M, Bragagnini C et al (2011) Paracrine signalling loops in adult human and mouse pancreatic islets: netrins modulate beta cell apoptosis signalling via dependence receptors. Diabetologia 54:828–842CrossRefPubMed
53.
go back to reference Yang YH, Manning Fox JE, Zhang KL, MacDonald PE, Johnson JD (2013) Intraislet SLIT-ROBO signaling is required for beta-cell survival and potentiates insulin secretion. Proc Natl Acad Sci U S A 110:16480–16485CrossRefPubMedPubMedCentral Yang YH, Manning Fox JE, Zhang KL, MacDonald PE, Johnson JD (2013) Intraislet SLIT-ROBO signaling is required for beta-cell survival and potentiates insulin secretion. Proc Natl Acad Sci U S A 110:16480–16485CrossRefPubMedPubMedCentral
54.
go back to reference Yang YH, Wills QF, Johnson JD (2015) A live-cell, high-content imaging survey of 206 endogenous factors across five stress conditions reveals context-dependent survival effects in mouse primary beta cells. Diabetologia 58:1239–1249CrossRefPubMedPubMedCentral Yang YH, Wills QF, Johnson JD (2015) A live-cell, high-content imaging survey of 206 endogenous factors across five stress conditions reveals context-dependent survival effects in mouse primary beta cells. Diabetologia 58:1239–1249CrossRefPubMedPubMedCentral
55.
go back to reference Vomund AN, Zinselmeyer BH, Hughes J et al (2015) Beta cells transfer vesicles containing insulin to phagocytes for presentation to T cells. Proc Natl Acad Sci U S A 112:E5496–E5502CrossRefPubMedPubMedCentral Vomund AN, Zinselmeyer BH, Hughes J et al (2015) Beta cells transfer vesicles containing insulin to phagocytes for presentation to T cells. Proc Natl Acad Sci U S A 112:E5496–E5502CrossRefPubMedPubMedCentral
56.
go back to reference Halban PA, Wollheim CB, Blondel B, Meda P, Niesor EN, Mintz DH (1982) The possible importance of contact between pancreatic islet cells for the control of insulin release. Endocrinology 111:86–94CrossRefPubMed Halban PA, Wollheim CB, Blondel B, Meda P, Niesor EN, Mintz DH (1982) The possible importance of contact between pancreatic islet cells for the control of insulin release. Endocrinology 111:86–94CrossRefPubMed
57.
go back to reference Benninger RK, Head WS, Zhang M, Satin LS, Piston DW (2011) Gap junctions and other mechanisms of cell-cell communication regulate basal insulin secretion in the pancreatic islet. J Physiol 589:5453–5466CrossRefPubMedPubMedCentral Benninger RK, Head WS, Zhang M, Satin LS, Piston DW (2011) Gap junctions and other mechanisms of cell-cell communication regulate basal insulin secretion in the pancreatic islet. J Physiol 589:5453–5466CrossRefPubMedPubMedCentral
58.
go back to reference Nourmohammadzadeh M, Xing Y, Lee JW et al (2016) A microfluidic array for real-time live-cell imaging of human and rodent pancreatic islets. Lab Chip 16:1466–1472CrossRefPubMed Nourmohammadzadeh M, Xing Y, Lee JW et al (2016) A microfluidic array for real-time live-cell imaging of human and rodent pancreatic islets. Lab Chip 16:1466–1472CrossRefPubMed
59.
go back to reference Pedraza E, Karajic A, Raoux M et al (2015) Guiding pancreatic beta cells to target electrodes in a whole-cell biosensor for diabetes. Lab Chip 15:3880–3890CrossRefPubMed Pedraza E, Karajic A, Raoux M et al (2015) Guiding pancreatic beta cells to target electrodes in a whole-cell biosensor for diabetes. Lab Chip 15:3880–3890CrossRefPubMed
60.
go back to reference Yi L, Wang X, Dhumpa R, Schrell AM, Mukhitov N, Roper MG (2015) Integrated perfusion and separation systems for entrainment of insulin secretion from islets of Langerhans. Lab Chip 15:823–832CrossRefPubMedPubMedCentral Yi L, Wang X, Dhumpa R, Schrell AM, Mukhitov N, Roper MG (2015) Integrated perfusion and separation systems for entrainment of insulin secretion from islets of Langerhans. Lab Chip 15:823–832CrossRefPubMedPubMedCentral
61.
go back to reference Liu H, Yang H, Zhu D et al (2014) Systematically labeling developmental stage-specific genes for the study of pancreatic β-cell differentiation from human embryonic stem cells. Cell Res 24:1181–1200CrossRefPubMedPubMedCentral Liu H, Yang H, Zhu D et al (2014) Systematically labeling developmental stage-specific genes for the study of pancreatic β-cell differentiation from human embryonic stem cells. Cell Res 24:1181–1200CrossRefPubMedPubMedCentral
62.
go back to reference Konorov SO, Schulze HG, Gage BK et al (2015) Process analytical utility of Raman microspectroscopy in the directed differentiation of human pancreatic insulin-positive cells. Anal Chem 87:10762–10769CrossRefPubMed Konorov SO, Schulze HG, Gage BK et al (2015) Process analytical utility of Raman microspectroscopy in the directed differentiation of human pancreatic insulin-positive cells. Anal Chem 87:10762–10769CrossRefPubMed
63.
go back to reference Ye L, Robertson MA, Mastracci TL, Anderson RM (2016) An insulin signaling feedback loop regulates pancreas progenitor cell differentiation during islet development and regeneration. Dev Biol 409:354–369CrossRefPubMed Ye L, Robertson MA, Mastracci TL, Anderson RM (2016) An insulin signaling feedback loop regulates pancreas progenitor cell differentiation during islet development and regeneration. Dev Biol 409:354–369CrossRefPubMed
64.
go back to reference Duvillie B, Currie C, Chrones T et al (2002) Increased islet cell proliferation, decreased apoptosis, and greater vascularization leading to β-cell hyperplasia in mutant mice lacking insulin. Endocrinology 143:1530–1537PubMed Duvillie B, Currie C, Chrones T et al (2002) Increased islet cell proliferation, decreased apoptosis, and greater vascularization leading to β-cell hyperplasia in mutant mice lacking insulin. Endocrinology 143:1530–1537PubMed
65.
go back to reference Vendrame F, Pileggi A, Laughlin E et al (2010) Recurrence of type 1 diabetes after simultaneous pancreas-kidney transplantation, despite immunosuppression, is associated with autoantibodies and pathogenic autoreactive CD4 T cells. Diabetes 59:947–957CrossRefPubMedPubMedCentral Vendrame F, Pileggi A, Laughlin E et al (2010) Recurrence of type 1 diabetes after simultaneous pancreas-kidney transplantation, despite immunosuppression, is associated with autoantibodies and pathogenic autoreactive CD4 T cells. Diabetes 59:947–957CrossRefPubMedPubMedCentral
66.
go back to reference Hoesli CA, Raghuram K, Kiang RL et al (2011) Pancreatic cell immobilization in alginate beads produced by emulsion and internal gelation. Biotechnol Bioeng 108:424–434CrossRefPubMed Hoesli CA, Raghuram K, Kiang RL et al (2011) Pancreatic cell immobilization in alginate beads produced by emulsion and internal gelation. Biotechnol Bioeng 108:424–434CrossRefPubMed
67.
go back to reference Szabat M, Page MM, Panzhinskiy E et al (2016) Reduced insulin production relieves endoplasmic reticulum stress and induces β cell proliferation. Cell Metab 23:179–193CrossRefPubMed Szabat M, Page MM, Panzhinskiy E et al (2016) Reduced insulin production relieves endoplasmic reticulum stress and induces β cell proliferation. Cell Metab 23:179–193CrossRefPubMed
68.
69.
go back to reference Bruin JE, Saber N, Braun N et al (2015) Treating diet-induced diabetes and obesity with human embryonic stem cell-derived pancreatic progenitor cells and antidiabetic drugs. Stem Cell Rep 4:605–620CrossRef Bruin JE, Saber N, Braun N et al (2015) Treating diet-induced diabetes and obesity with human embryonic stem cell-derived pancreatic progenitor cells and antidiabetic drugs. Stem Cell Rep 4:605–620CrossRef
70.
go back to reference ACCORD Study Group (2016) Nine-year effects of 3.7 years of intensive glycemic control on cardiovascular outcomes. Diabetes Care 39:701–708CrossRef ACCORD Study Group (2016) Nine-year effects of 3.7 years of intensive glycemic control on cardiovascular outcomes. Diabetes Care 39:701–708CrossRef
71.
go back to reference Shanik MH, Xu Y, Skrha J, Dankner R, Zick Y, Roth J (2008) Insulin resistance and hyperinsulinemia: is hyperinsulinemia the cart or the horse? Diabetes Care 31(Suppl 2):S262–S268CrossRefPubMed Shanik MH, Xu Y, Skrha J, Dankner R, Zick Y, Roth J (2008) Insulin resistance and hyperinsulinemia: is hyperinsulinemia the cart or the horse? Diabetes Care 31(Suppl 2):S262–S268CrossRefPubMed
72.
go back to reference Johnson JD, Ao Z, Ao P et al (2009) Different effects of FK506, rapamycin, and mycophenolate mofetil on glucose-stimulated insulin release and apoptosis in human islets. Cell Transplant 18:833–845CrossRefPubMed Johnson JD, Ao Z, Ao P et al (2009) Different effects of FK506, rapamycin, and mycophenolate mofetil on glucose-stimulated insulin release and apoptosis in human islets. Cell Transplant 18:833–845CrossRefPubMed
Metadata
Title
The quest to make fully functional human pancreatic beta cells from embryonic stem cells: climbing a mountain in the clouds
Author
James D. Johnson
Publication date
01-10-2016
Publisher
Springer Berlin Heidelberg
Published in
Diabetologia / Issue 10/2016
Print ISSN: 0012-186X
Electronic ISSN: 1432-0428
DOI
https://doi.org/10.1007/s00125-016-4059-4

Other articles of this Issue 10/2016

Diabetologia 10/2016 Go to the issue