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Modelling the endocrine pancreas in health and disease

Abstract

Diabetes mellitus is a multifactorial disease affecting increasing numbers of patients worldwide. Progression to insulin-dependent diabetes mellitus is characterized by the loss or dysfunction of pancreatic β-cells, but the pathomechanisms underlying β-cell failure in type 1 diabetes mellitus and type 2 diabetes mellitus are still poorly defined. Regeneration of β-cell mass from residual islet cells or replacement by β-like cells derived from stem cells holds great promise to stop or reverse disease progression. However, the development of new treatment options is hampered by our limited understanding of human pancreas organogenesis due to the restricted access to primary tissues. Therefore, the challenge is to translate results obtained from preclinical model systems to humans, which requires comparative modelling of β-cell biology in health and disease. Here, we discuss diverse modelling systems across different species that provide spatial and temporal resolution of cellular and molecular mechanisms to understand the evolutionary conserved genotype–phenotype relationship and translate them to humans. In addition, we summarize the latest knowledge on organoids, stem cell differentiation platforms, primary micro-islets and pseudo-islets, bioengineering and microfluidic systems for studying human pancreas development and homeostasis ex vivo. These new modelling systems and platforms have opened novel avenues for exploring the developmental trajectory, physiology, biology and pathology of the human pancreas.

Key points

  • The evolutionary differences in pancreas development, function and failure undermine the translation of successful preclinical studies from animal models to humans.

  • Establishing novel therapeutic approaches for treatment of diabetes mellitus requires comprehensive understanding of human endocrine pancreas formation and function.

  • The proper development of endocrine cells relies on the tight coupling of morphogenetic events with cell differentiation programmes.

  • 3D organoids and stem cell differentiation systems provide unique platforms for modelling human endocrine cell morphogenesis and differentiation.

  • Large animals, such as minipigs, offer novel systems for modelling diabetes mellitus closely to the disease development and progression in humans.

  • Establishing organizations that provide human primary pancreatic samples that are healthy or have diabetes mellitus have increased our understanding of pathomechanism of diabetes mellitus.

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Fig. 1: Early pancreas development, endocrine cell formation and clustering.
Fig. 2: 3D organoid systems for modelling human pancreatic morphogenesis and differentiation.
Fig. 3: In vitro modelling systems to assess β-cell function.
Fig. 4: The pig as a translational animal model to systematically study β-cell formation, maturation, function and failure.

References

  1. Katsarou, A. et al. Type 1 diabetes mellitus. Nat. Rev. Dis. Prim. 3, 17016 (2017).

    PubMed  Article  Google Scholar 

  2. DeFronzo, R. A. et al. Type 2 diabetes mellitus. Nat. Rev. Dis. Prim. 1, 15019 (2015).

    PubMed  Article  Google Scholar 

  3. Keenan, H. A. et al. Residual insulin production and pancreatic ß-cell turnover after 50 years of diabetes: Joslin Medalist study. Diabetes 59, 2–9 (2010).

    Article  CAS  Google Scholar 

  4. Huang, T. et al. Pancreatic islet regeneration through PDX-1/Notch-1/Ngn3 signaling after gastric bypass surgery in db/db mice. Exp. Ther. Med. 14, 2831–2838 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  5. Zhou, X. et al. Pancreatic hyperplasia after gastric bypass surgery in a GK rat model of non-obese type 2 diabetes. J. Endocrinol. 228, 13–23 (2016).

    CAS  PubMed  Article  Google Scholar 

  6. Taylor, R. et al. Remission of human type 2 diabetes requires decrease in liver and pancreas fat content but is dependent upon capacity for β cell recovery. Cell Metab. 28, 547–556 (2018).

    CAS  PubMed  Article  Google Scholar 

  7. Shapiro, A. M. J. et al. International trial of the edmonton protocol for islet transplantation. N. Engl. J. Med. 355, 1318–1330 (2006).

    CAS  PubMed  Article  Google Scholar 

  8. Zorn, A. M. & Wells, J. M. Vertebrate endoderm development and organ formation. Annu. Rev. Cell Dev. Biol. 25, 221–251 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  9. Zorn, A. M. & Wells, J. M. Molecular basis of vertebrate endoderm development. Int. Rev. Cytol. 259, 49–111 (2007).

    CAS  PubMed  Article  Google Scholar 

  10. Stainier, D. Y. R. A glimpse into the molecular entrails of endoderm formation. Genes Dev. 16, 893–907 (2002).

    CAS  PubMed  Article  Google Scholar 

  11. Singh, S. P. et al. Different developmental histories of beta-cells generate functional and proliferative heterogeneity during islet growth. Nat. Commun. 8, 664 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  12. Jennings, R. E. et al. Development of the human pancreas from foregut to endocrine commitment. Diabetes 62, 3514–3522 (2013). A comprehensive study on early stages of human pancreas development.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  13. Jennings, R. E., Berry, A. A., Strutt, J. P., Gerrard, D. T. & Hanley, N. A. Human pancreas development. Development 142, 3126–3137 (2015).

    CAS  PubMed  Article  Google Scholar 

  14. Pan, F. C. & Brissova, M. Pancreas development in humans. Curr. Opin. Endocrinol. Diabetes. Obes. 21, 77–82 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  15. Jennings, R. E. et al. Laser capture and deep sequencing reveals the transcriptomic programmes regulating the onset of pancreas and liver differentiation in human embryos. Stem Cell Rep. 9, 1387–1394 (2017).

    CAS  Article  Google Scholar 

  16. Leiter, E. H. & Von Herrath, M. Animal models have little to teach us about type 1 diabetes: 2. In opposition to this proposal. Diabetologia 47, 1657–1660 (2004).

    CAS  PubMed  Article  Google Scholar 

  17. Roep, B. O. & Atkinson, M. Animal models have little to teach us about type 1 diabetes: 1. In support of this proposal. Diabetologia 47, 1650–1656 (2004).

    CAS  PubMed  Article  Google Scholar 

  18. Pagliuca, F. W. et al. Generation of functional human pancreatic beta cells in vitro. Cell 159, 428–439 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  19. Russ, H. a et al. Controlled induction of human pancreatic progenitors produces functional beta-like cells in vitro. EMBO J. 34, 1759–1772 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  20. Rezania, A. et al. Reversal of diabetes with insulin-producing cells derived in vitro from human pluripotent stem cells. Nat. Biotechnol. 32, 1121–1133 (2014). One of the first well-established protocols for in vitro generation of pancreatic β-like cells that is used extensively by many different laboratories worldwide.

    CAS  Article  PubMed  Google Scholar 

  21. Amour, K. A. D. et al. Production of pancreatic hormone-expressing endocrine cells from human embryonic stem cells. Nat. Biotechnol. 24, 1392–1401 (2006).

    PubMed  Article  CAS  Google Scholar 

  22. Roscioni, S. S., Migliorini, A., Gegg, M. & Lickert, H. Impact of islet architecture on β-cell heterogeneity, plasticity and function. Nat. Rev. Endocrinol. 12, 695–709 (2016).

    CAS  Article  PubMed  Google Scholar 

  23. Bastidas-Ponce, A., Scheibner, K., Lickert, H. & Bakhti, M. Cellular and molecular mechanisms coordinating pancreas development. Development 144, 2873–2888 (2017).

    CAS  PubMed  Article  Google Scholar 

  24. Pan, F. C. & Wright, C. Pancreas organogenesis: from bud to plexus to gland. Dev. Dyn. 240, 530–565 (2011).

    CAS  PubMed  Article  Google Scholar 

  25. Shih, H. P., Wang, A. & Sander, M. Pancreas organogenesis: from lineage determination to morphogenesis. Annu. Rev. Cell Dev. Biol. 29, 81–105 (2013).

    CAS  PubMed  Article  Google Scholar 

  26. Larsen, H. L. & Grapin-Botton, A. The molecular and morphogenetic basis of pancreas organogenesis. Semin. Cell Dev. Biol. 66, 51–68 (2017).

    CAS  PubMed  Article  Google Scholar 

  27. Röder, P. V., Wu, B., Liu, Y. & Han, W. Pancreatic regulation of glucose homeostasis. Exp. Mol. Med. 48, e219 (2016).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  28. Suissa, Y. et al. Gastrin: a distinct fate of neurogenin3 positive progenitor cells in the embryonic pancreas. PLOS ONE 8, e70397 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  29. Arnes, L., Hill, J. T., Gross, S., Magnuson, M. A. & Sussel, L. Ghrelin expression in the mouse pancreas defines a unique multipotent progenitor population. PLOS ONE 7, e52026 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  30. Gittes, G. K. Developmental biology of the pancreas: a comprehensive review. Dev. Biol. 326, 4–35 (2009).

    CAS  PubMed  Article  Google Scholar 

  31. Kesavan, G. et al. Cdc42-mediated tubulogenesis controls cell specification. Cell 139, 791–801 (2009). The first study about the molecular mechanism underlying the formation of the pancreatic epithelial network during development; this study highlights the crosstalk between cell polarity and differentiation during pancreas development.

    CAS  PubMed  Article  Google Scholar 

  32. Villasenor, A., Chong, D. C., Henkemeyer, M. & Cleaver, O. Epithelial dynamics of pancreatic branching morphogenesis. Development 137, 4295–4305 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  33. Bankaitis, E. D., Bechard, M. E. & Wright, C. V. E. Feedback control of growth, differentiation, and morphogenesis of pancreatic endocrine progenitors in an epithelial plexus niche. Genes Dev. 29, 2203–2216 (2015). The first study that analyses the formation and characteristics of the plexus niche within embryonic pancreatic epithelium.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  34. Gradwohl, G., Dierich, A., LeMeur, M. & Guillemot, F. Neurogenin3 is required for the development of the four endocrine cell lineages of the pancreas. Proc. Natl Acad. Sci. USA 97, 1607–1611 (2000).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  35. Gu, G., Dubauskaite, J. & Melton, D. A. Direct evidence for the pancreatic lineage: NGN3+ cells are islet progenitors and are distinct from duct progenitors. Development 129, 2447–2457 (2002).

    CAS  PubMed  Article  Google Scholar 

  36. Gouzi, M., Kim, Y. H., Katsumoto, K., Johansson, K. & Grapin-Botton, A. Neurogenin3 initiates stepwise delamination of differentiating endocrine cells during pancreas development. Dev. Dyn. 240, 589–604 (2011).

    CAS  PubMed  Article  Google Scholar 

  37. Cleaver, O. & Dor, Y. Vascular instruction of pancreas development. Development 139, 2833–2843 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  38. Thorens, B. Neural regulation of pancreatic islet cell mass and function. Diabetes Obes. Metab. 16, 87–95 (2014).

    CAS  PubMed  Article  Google Scholar 

  39. Slack, J. M. W. Developmental biology of the pancreas. Development 121, 1569–1580 (1995).

    CAS  PubMed  Article  Google Scholar 

  40. Polak, M., Bouchareb-Banaei, L., Scharfmann, R. & Czernichow, P. Early pattern of differentiation in the human pancreas. Diabetes 49, 225–232 (2000).

    CAS  PubMed  Article  Google Scholar 

  41. Churchill, A. J. et al. Genetic evidence that Nkx2.2 acts primarily downstream of Neurog3 in pancreatic endocrine lineage development. eLife 6, e20010 (2017).

    PubMed  PubMed Central  Article  Google Scholar 

  42. Anderson, K. R., White, P., Kaestner, K. H. & Sussel, L. Identification of known and novel pancreas genes expressed downstream of Nkx2.2 during development. BMC Dev. Biol. 9, 65 (2009).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  43. Salisbury, R. J. et al. The window period of NEUROGENIN3 during human gestation. Islets 6, e954436 (2014).

    PubMed  PubMed Central  Article  Google Scholar 

  44. Jeon, J., Correa-Medina, M., Ricordi, C., Edlund, H. & Diez, J. A. Endocrine cell clustering during human pancreas development. J. Histochem. Cytochem. 57, 811–824 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  45. Ramond, C. et al. Understanding human fetal pancreas development using subpopulation sorting, RNA sequencing and single-cell profiling. Development 145, dev165480 (2018).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  46. Ramond, C. et al. Reconstructing human pancreatic differentiation by mapping specific cell populations during development. eLife 6, e27564 (2017).

    PubMed  PubMed Central  Article  Google Scholar 

  47. Billings, L. K. & Florez, J. C. The genetics of type 2 diabetes: what have we learned from GWAS? Ann. NY Acad. Sci. 1212, 59–77 (2010).

    CAS  PubMed  Article  Google Scholar 

  48. Pociot, F. Type 1 diabetes genome-wide association studies: not to be lost in translation. Clin. Transl Immunol. 6, e162 (2017).

    Article  CAS  Google Scholar 

  49. Sladek, R. et al. A genome-wide association study identifies novel risk loci for type 2 diabetes. Nature 445, 881–885 (2007).

    CAS  PubMed  Article  Google Scholar 

  50. Saxena, R. et al. Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels. Science 316, 1331–1336 (2007).

    CAS  PubMed  Article  Google Scholar 

  51. Morris, A. P. et al. Large-scale association analysis provides insights into the genetic architecture and pathophysiology of type 2 diabetes. Nat. Genet. 44, 981–990 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  52. Mahajan, A. et al. Genome-wide trans-ancestry meta-analysis provides insight into the genetic architecture of type 2 diabetes susceptibility. Nat. Genet. 46, 234–244 (2014).

    CAS  PubMed  Article  Google Scholar 

  53. Owen, K. R. Monogenic diabetes in adults: what are the new developments? Curr. Opin. Genet. Dev. 50, 103–110 (2018).

    CAS  PubMed  Article  Google Scholar 

  54. Meier, J. J. et al. β-Cell replication is the primary mechanism subserving the postnatal expansion of β-cell mass in humans. Diabetes 57, 1584–1594 (2008).

    CAS  PubMed  Article  Google Scholar 

  55. Heuvel-Borsboom, H., de Valk, H. W., Losekoot, M. & Westerink, J. Maturity onset diabetes of the young: seek and you will find. Neth. J. Med. 74, 193–200 (2016).

    CAS  PubMed  Google Scholar 

  56. Shi, Z.-D. et al. Genome editing in hPSCs reveals GATA6 haploinsufficiency and a genetic interaction with GATA4 in human pancreatic development. Cell Stem Cell 20, 675–688 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  57. Teo, A. K. K. et al. Early developmental perturbations in a human stem cell model of MODY5/HNF1B pancreatic hypoplasia. Stem Cell Rep. 6, 357–367 (2016).

    CAS  Article  Google Scholar 

  58. Bastidas-Ponce, A. et al. Foxa2 and Pdx1 cooperatively regulate postnatal maturation of pancreatic β-cells. Mol. Metab. 6, 524–534 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  59. Liu, J. S. E. & Hebrok, M. All mixed up: defining roles for β-cell subtypes in mature islets. Genes Dev. 31, 228–240 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  60. Avrahami, D. et al. β-Cells are not uniform after all—novel insights into molecular heterogeneity of insulin-secreting cells. Diabetes Obes. Metab. 19, 147–152 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  61. Nasteska, D. & Hodson, D. J. The role of beta cell heterogeneity in islet function and insulin release. J. Mol. Endocrinol. 61, R43–R60 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  62. Johnston, N. R. et al. Beta cell hubs dictate pancreatic islet responses to glucose. Cell Metab. 24, 389–401 (2016). This study proves the existence of specialized β-cells that coordinate islet oscillatory behaviour.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  63. Campanale, J. P., Sun, T. Y. & Montell, D. J. Development and dynamics of cell polarity at a glance. J. Cell Sci. 130, 1201–1207 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  64. Bader, E. et al. Identification of proliferative and mature β-cells in the islets of langerhans. Nature 535, 430–434 (2016). The first study that presents the molecular marker for β-cell heterogeneity in mouse pancreas.

    CAS  Article  PubMed  Google Scholar 

  65. Cortijo, C., Gouzi, M., Tissir, F. & Grapin-Botton, A. Planar cell polarity controls pancreatic beta cell differentiation and glucose homeostasis. Cell Rep. 2, 1593–1606 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  66. Dorrell, C. et al. Human islets contain four distinct subtypes of β cells. Nat. Commun. 7, 11756 (2016). The first study that reveals distinct surface markers distinguishing different human β-cell populations.

    PubMed  PubMed Central  Article  Google Scholar 

  67. Wang, Y. J. et al. Single-cell mass cytometry analysis of the human endocrine pancreas. Cell Metab. 24, 616–626 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  68. Oram, R. A. et al. The majority of patients with long-duration type 1 diabetes are insulin microsecretors and have functioning beta cells. Diabetologia 57, 187–191 (2014).

    CAS  PubMed  Article  Google Scholar 

  69. Butler, A. E. et al. Beta-cell deficit and increased beta-cell apoptosis in humans with type 2 diabetes. Diabetes 52, 102–110 (2003).

    CAS  PubMed  Article  Google Scholar 

  70. Cinti, F. et al. Evidence of β-cell dedifferentiation in human type 2 diabetes. J. Clin. Endocrinol. Metab. 101, 1044–1054 (2016).

    CAS  PubMed  Article  Google Scholar 

  71. Dhawan, S., Dirice, E., Kulkarni, R. N. & Bhushan, A. Inhibition of TGF-β signaling promotes human pancreatic β-cell replication. Diabetes 65, 1208–1218 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  72. El Ouaamari, A. et al. SerpinB1 promotes pancreatic β cell proliferation. Cell Metab. 23, 194–205 (2016).

    CAS  PubMed  Article  Google Scholar 

  73. Wang, P. et al. A high-throughput chemical screen reveals that harmine-mediated inhibition of DYRK1A increases human pancreatic beta cell replication. Nat. Med. 21, 383–388 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  74. Puri, S. et al. Replication confers β cell immaturity. Nat. Commun. 9, 485 (2018).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  75. Rui, J. et al. β cells that resist immunological attack develop during progression of autoimmune diabetes in NOD mice. Cell Metab. 25, 727–738 (2017). Reports that a subpopulation of β-cells can resist immune-mediated killing and might explain why residual β-cells exist in some patients with T1DM.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  76. Wasserfall, C. et al. Persistence of pancreatic insulin mRNA expression and proinsulin protein in type 1 diabetes pancreata. Cell Metab. 26, 568–575 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  77. Talchai, C., Xuan, S., Lin, H. V., Sussel, L. & Accili, D. Pancreatic β cell dedifferentiation as a mechanism of diabetic β cell failure. Cell 150, 1223–1234 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  78. Wang, Z., York, N. W., Nichols, C. G. & Remedi, M. S. Pancreatic β cell dedifferentiation in diabetes and redifferentiation following insulin therapy. Cell Metab. 19, 872–882 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  79. Evers, S. S., Sandoval, D. A. & Seeley, R. J. The physiology and molecular underpinnings of the effects of bariatric surgery on obesity and diabetes. Annu. Rev. Physiol. 79, 313–334 (2017).

    CAS  PubMed  Article  Google Scholar 

  80. Solar, M. et al. Pancreatic exocrine duct cells give rise to insulin-producing beta cells during embryogenesis but not after birth. Dev. Cell 17, 849–860 (2009).

    CAS  PubMed  Article  Google Scholar 

  81. Zhou, Q. et al. A multipotent progenitor domain guides pancreatic organogenesis. Dev. Cell 13, 103–114 (2007).

    CAS  PubMed  Article  Google Scholar 

  82. Schaffer, A. E., Freude, K. K., Nelson, S. B. & Sander, M. Nkx6 transcription factors and Ptf1a function as antagonistic lineage determinants in multipotent pancreatic progenitors. Dev. Cell 18, 1022–1029 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  83. Kim, Y. H. et al. Cell cycle–dependent differentiation dynamics balances growth and endocrine differentiation in the pancreas. PLOS Biol. 13, e1002111 (2015).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  84. Bechard, M. E. et al. Precommitment low-level Neurog3 expression defines a long-lived mitotic endocrine-biased progenitor pool that drives production of endocrine-committed cells. Genes Dev. 30, 1852–1865 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  85. Apelqvist, A. Notch signalling controls pancreatic cell differentiation. Nature 400, 877–881 (1999).

    CAS  PubMed  Article  Google Scholar 

  86. Shih, H. P. et al. A Notch-dependent molecular circuitry initiates pancreatic endocrine and ductal cell differentiation. Development 139, 2488–2499 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  87. Larsen, B. M., Hrycaj, S. M., Newman, M., Li, Y. & Wellik, D. M. Mesenchymal Hox6 function is required for pancreatic endocrine cell differentiation. Development 142, 3859–3868 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Serafimidis, I. et al. Pancreas lineage allocation and specification are regulated by sphingosine-1-phosphate signalling. PLOS Biol. 15, e2000949 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  89. Löf-Öhlin, Z. M. et al. EGFR signalling controls cellular fate and pancreatic organogenesis by regulating apicobasal polarity. Nat. Cell Biol. 19, 1313–1325 (2017). This study shows the direct impact of epithelial polarity and morphogenesis on endocrine cell induction and differentiation.

    PubMed  Article  CAS  Google Scholar 

  90. Johansson, K. A. et al. Temporal control of neurogenin3 activity in pancreas progenitors reveals competence windows for the generation of different endocrine cell types. Dev. Cell 12, 457–465 (2007).

    CAS  Article  PubMed  Google Scholar 

  91. Rukstalis, J. M. & Habener, J. F. Snail2, a mediator of epithelial-mesenchymal transitions, expressed in progenitor cells of the developing endocrine pancreas. Gene Expr. Patterns 7, 471–479 (2007).

    CAS  PubMed  Article  Google Scholar 

  92. Kesavan, G. et al. Cdc42/N-WASP signaling links actin dynamics to pancreatic cell delamination and differentiation. Development 141, 685–696 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  93. Miettinen, P. J. et al. Impaired migration and delayed differentiation of pancreatic islet cells in mice lacking EGF-receptors. Development 127, 2617–2627 (2000).

    CAS  PubMed  Article  Google Scholar 

  94. Freudenblum, J. et al. In vivo imaging of emerging endocrine cells reveals a requirement for PI3K-regulated motility in pancreatic islet morphogenesis. Development 145, dev158477 (2018).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  95. Pauerstein, P. T. et al. A radial axis defined by semaphorin-to-neuropilin signaling controls pancreatic islet morphogenesis. Development 144, 3744–3754 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Clevers, H. Modeling development and disease with organoids. Cell 165, 1586–1597 (2016).

    CAS  PubMed  Article  Google Scholar 

  97. Lancaster, M. A. & Knoblich, J. A. Organogenesisin a dish: modeling development and disease using organoid technologies. Science 345, 1247125 (2014).

    Article  CAS  PubMed  Google Scholar 

  98. Kretzschmar, K. & Clevers, H. Organoids: modeling development and the stem cell niche in a dish. Dev. Cell 38, 590–600 (2016).

    CAS  PubMed  Article  Google Scholar 

  99. Dahl-Jensen, S. & Grapin-Botton, A. The physics of organoids: a biophysical approach to understanding organogenesis. Development 144, 946–951 (2017).

    CAS  PubMed  Article  Google Scholar 

  100. Eiraku, M. et al. Self-organizing optic-cup morphogenesis in three-dimensional culture. Nature 472, 51–56 (2011).

    CAS  PubMed  Article  Google Scholar 

  101. Sato, T. et al. Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche. Nature 459, 262–265 (2009).

    CAS  Article  PubMed  Google Scholar 

  102. Huch, M. & Koo, B.-K. Modeling mouse and human development using organoid cultures. Development 142, 3113–3125 (2015).

    CAS  PubMed  Article  Google Scholar 

  103. Hindley, C. J., Cordero-Espinoza, L. & Huch, M. Organoids from adult liver and pancreas: stem cell biology and biomedical utility. Dev. Biol. 420, 251–261 (2016).

    CAS  PubMed  Article  Google Scholar 

  104. Greggio, C. et al. Artificial three-dimensional niches deconstruct pancreas development in vitro. Development 140, 4452–4462 (2013). The first study to generate pancreatic organoids from mouse embryonic pancreatic cells.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  105. Sugiyama, T. et al. Reconstituting pancreas development from purified progenitor cells reveals genes essential for islet differentiation. Proc. Natl Acad. Sci. USA 110, 12691–12696 (2013).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  106. Bonfanti, P. et al. Ex vivo expansion and differentiation of human and mouse fetal pancreatic progenitors are modulated by epidermal growth factor. Stem Cells Dev. 24, 1766–1778 (2015).

    CAS  PubMed  Article  Google Scholar 

  107. Hohwieler, M. et al. Human pluripotent stem cell-derived acinar/ductal organoids generate human pancreas upon orthotopic transplantation and allow disease modelling. Gut 66, 473–486 (2017).

    CAS  PubMed  Article  Google Scholar 

  108. Jin, L. et al. Colony-forming cells in the adult mouse pancreas are expandable in Matrigel and form endocrine/acinar colonies in laminin hydrogel. Proc. Natl Acad. Sci. USA 110, 3907–3912 (2013).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  109. Jin, L. et al. In vitro multilineage differentiation and self-renewal of single pancreatic colony-forming cells from adult C57Bl/6 mice. Stem Cells Dev. 23, 899–909 (2014).

    CAS  PubMed  Article  Google Scholar 

  110. Huch, M. et al. Unlimited in vitro expansion of adult bi-potent pancreas progenitors through the Lgr5/R-spondin axis. EMBO J. 32, 2708–2721 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  111. Lee, J. et al. Expansion and conversion of human pancreatic ductal cells into insulin-secreting endocrine cells. eLife 2, e00940 (2013).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  112. Loomans, C. J. M. et al. Expansion of adult human pancreatic tissue yields organoids harboring progenitor cells with endocrine differentiation potential. Stem Cell Rep. 10, 1088–1101 (2018).

    Article  CAS  Google Scholar 

  113. Sander, J. D. & Joung, J. K. CRISPR-Cas systems for editing, regulating and targeting genomes. Nat. Biotechnol. 32, 347–355 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  114. Shapiro, A. M. et al. Islet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen. N. Engl. J. Med. 343, 230–238 (2000).

    CAS  PubMed  Article  Google Scholar 

  115. Bruni, A., Gala-Lopez, B., Pepper, A. R., Abualhassan, N. S. & James Shapiro, A. M. Islet cell transplantation for the treatment of type 1 diabetes: recent advances and future challenges. Diabetes Metab. Syndr. Obes. 23, 211–223 (2014).

    Google Scholar 

  116. Assady, S. et al. Insulin production by human embryonic stem cells. Diabetes 50, 1691–1697 (2001).

    CAS  PubMed  Article  Google Scholar 

  117. Hrvatin, S. et al. Differentiated human stem cells resemble fetal, not adult, β cells. Proc. Natl Acad. Sci. USA 111, 3038–3043 (2014).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  118. Haghverdi, L., Büttner, M., Wolf, F. A., Buettner, F. & Theis, F. J. Diffusion pseudotime robustly reconstructs lineage branching. Nat. Methods 13, 845–848 (2016).

    CAS  PubMed  Article  Google Scholar 

  119. Griffiths, J. A., Scialdone, A. & Marioni, J. C. Using single-cell genomics to understand developmental processes and cell fate decisions. Mol. Syst. Biol. 14, e8046 (2018).

    PubMed  PubMed Central  Article  Google Scholar 

  120. Petersen, M. B. K. et al. Single-cell gene expression analysis of a human ESC model of pancreatic endocrine development reveals different paths to β-cell differentiation. Stem Cell Rep. 9, 1246–1261 (2017).

    CAS  Article  Google Scholar 

  121. Cogger, K. F. et al. Glycoprotein 2 is a specific cell surface marker of human pancreatic progenitors. Nat. Commun. 8, 331 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  122. Ameri, J. et al. Efficient generation of glucose-responsive beta cells from isolated GP2+ human pancreatic progenitors. Cell Rep. 19, 36–49 (2017).

    CAS  Article  PubMed  Google Scholar 

  123. Leibiger, I. B. & Berggren, P. O. Intraocular in vivo imaging of pancreatic islet cell physiology/pathology. Mol. Metab. 6, 1002–1009 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  124. Brissova, M. et al. Assessment of human pancreatic islet architecture and composition by laser scanning confocal microscopy. J. Histochem. Cytochem. 53, 1087–1097 (2005).

    CAS  PubMed  Article  Google Scholar 

  125. Steiner, D. J., Kim, A., Miller, K. & Hara, M. Pancreatic islet plasticity: interspecies comparison of islet architecture and composition. Islets 2, 135–145 (2010).

    PubMed  Article  Google Scholar 

  126. Chambers, A. P. et al. The role of pancreatic preproglucagon in glucose homeostasis in mice. Cell Metab. 25, 927–934 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  127. Drucker, D. J. Mechanisms of action and therapeutic application of glucagon-like peptide-1. Cell Metab. 27, 740–756 (2018).

    CAS  PubMed  Article  Google Scholar 

  128. van der Meulen, T. & Huising, M. O. Role of transcription factors in the transdifferentiation of pancreatic islet cells. J. Mol. Endocrinol. 54, R103–R117 (2015).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  129. DiGruccio, M. R. et al. Comprehensive alpha, beta and delta cell transcriptomes reveal that ghrelin selectively activates delta cells and promotes somatostatin release from pancreatic islets. Mol. Metab. 5, 449–458 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  130. Brissova, M. et al. α cell function and gene expression are compromised in type 1 diabetes. Cell Rep. 6, 2667–2676 (2018).

    Article  CAS  Google Scholar 

  131. Kao, D. I. et al. Endothelial cells control pancreatic cell fate at defined stages through EGFl7 signaling. Stem Cell Rep. 4, 181–189 (2015).

    CAS  Article  Google Scholar 

  132. Aamodt, K. I. & Powers, A. C. Signals in the pancreatic islet microenvironment influence β-cell proliferation. Diabetes Obes. Metab. 19, 124–136 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  133. Camp, J. G. et al. Multilineage communication regulates human liver bud development from pluripotency. Nature 546, 533–538 (2017). This study shows the dissection of interlineage communication in human liver bud development by single-cell RNA sequencing.

    CAS  PubMed  Article  Google Scholar 

  134. Wang, X. et al. Genome-wide analysis of PDX1 target genes in human pancreatic progenitors. Mol. Metab. 9, 57–68 (2018).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  135. Kondo, Y., Toyoda, T., Inagaki, N. & Osafune, K. iPSC technology-based regenerative therapy for diabetes. J. Diabetes Invest. 9, 234–243 (2018).

    Article  Google Scholar 

  136. Teo, A. K. K., Gupta, M. K., Doria, A. & Kulkarni, R. N. Dissecting diabetes/metabolic disease mechanisms using pluripotent stem cells and genome editing tools. Mol. Metab. 4, 593–604 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  137. Iovino, S. et al. Genetic insulin resistance is a potent regulator of gene expression and proliferation in human iPS cells. Diabetes 63, 4130–4142 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  138. Tiyaboonchai, A. et al. GATA6 plays an important role in the induction of human definitive endoderm, development of the pancreas, and Functionality of pancreatic β cells. Stem Cell Reports 8, 589–604 (2017).

  139. Carrasco, M., Delgado, I., Soria, B., Martín, F. & Rojas, A. GATA4 and GATA6 control mouse pancreas organogenesis. J. Clin. Invest. 122, 3504–3515 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  140. Xuan, S. et al. Pancreas-specific deletion of mouse Gata4 and Gata6 causes pancreatic agenesis. J. Clin. Invest. 122, 3516–3528 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  141. Shang, L. et al. β-cell dysfunction due to increased ER stress in a stem cell model of wolfram syndrome. Diabetes 63, 923–933 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  142. Sagen, J. V. et al. Permanent neonatal diabetes due to mutations in KCNJ11 encoding Kir6.2: patient characteristics and initial response to sulfonylurea therapy. Diabetes 53, 2713–2718 (2004).

    CAS  PubMed  Article  Google Scholar 

  143. Gloyn, A. L. et al. Activating mutations in the gene encoding the ATP-sensitive potassium-channel subunit Kir6.2 and permanent neonatal diabetes. N. Engl. J. Med. 350, 1838–1849 (2004).

    CAS  PubMed  Article  Google Scholar 

  144. Reissaus, C. A. & Piston, D. W. Reestablishment of glucose inhibition of glucagon secretion in small pseudoislets. Diabetes 66, 960–969 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  145. Halban, P. A., Powers, S. L., George, K. L. & Bonner-Weir, S. Spontaneous reassociation of dispersed adult rat pancreatic islet cells into aggregates with three-dimensional architecture typical of native islets. Diabetes 36, 783–790 (1987).

    CAS  PubMed  Article  Google Scholar 

  146. Yesildag, B. et al. Using uniform reaggregated pancreatic islets in a microfluidic perifusion system enables studying insulin release dynamics at single-islet level. ethz.ch https://www.research-collection.ethz.ch/handle/20.500.11850/237502 (2017).

  147. Marciniak, A. et al. Using pancreas tissue slices for in situ studies of islet of Langerhans and acinar cell biology. Nat. Protoc. 9, 2809–2822 (2014).

    CAS  PubMed  Article  Google Scholar 

  148. Speier, S. et al. Noninvasive in vivo imaging of pancreatic islet cell biology. Nat. Med. 14, 574–578 (2008). This study establishes a technique to transplant isolated islets into the anterior chamber of the eye, allowing live imaging of pancreatic islets in vivo.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  149. Miyazaki, J. et al. Establishment of a pancreatic b cell line that retains glucose inducible insulin secretion: special reference to expression of glucose transporter isoforms. Endocrinology 127, 126–132 (1990).

    CAS  PubMed  Article  Google Scholar 

  150. Asfari, M. et al. Establishment of 2-mercaptoethanol-dependent differentiated insulin-secreting cell lines. Endocrinology 130, 167–178 (1992).

    CAS  PubMed  Article  Google Scholar 

  151. Iwasaki, M. et al. Establishment of new clonal pancreatic β-cell lines (MIN6-K) useful for study of incretin/cyclic adenosine monophosphate signaling. J. Diabetes Investig. 1, 137–142 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  152. Ravassard, P. et al. A genetically engineered human pancreatic β cell line exhibiting glucose-inducible insulin secretion. J. Clin. Invest. 121, 3589–3597 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  153. Scharfmann, R. & Pechberty, S. Development of a conditionally immortalized human pancreatic β cell line. J. Clin. Invest. 124, 2087–2098 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  154. Benazra, M. et al. A human beta cell line with drug inducible excision of immortalizing transgenes. Mol. Metab. 4, 916–925 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  155. Tsonkova, V. G. et al. The EndoC-βH1 cell line is a valid model of human beta cells and applicable for screenings to identify novel drug target candidates. Mol. Metab. 8, 144–157 (2018).

    CAS  PubMed  Article  Google Scholar 

  156. Hakonen, E. et al. MANF protects human pancreatic beta cells against stress-induced cell death. Diabetologia 61, 2202–2214 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  157. Diedisheim, M. et al. Modeling human pancreatic beta cell dedifferentiation. Mol. Metab. 10, 74–86 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  158. Lecomte, M.-J. et al. Aggregation of engineered human β-cells into pseudoislets: insulin secretion and gene expression profile in normoxic and hypoxic milieu. Cell. Med. 8, 99–112 (2016).

    PubMed  PubMed Central  Article  Google Scholar 

  159. Skrzypek, K., Barrera, Y. B., Groth, T. & Stamatialis, D. Endothelial and beta cell composite aggregates for improved function of a bioartificial pancreas encapsulation device. Int. J. Artif. Organs 41, 152–159 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  160. Spelios, M. G., Afinowicz, L. A., Tipon, R. C. & Akirav, E. M. Human EndoC-βH1 β-cells form pseudoislets with improved glucose sensitivity and enhanced GLP-1 signaling in the presence of islet-derived endothelial cells. Am. J. Physiol. Metab. 314, E512–E521 (2018).

    CAS  Google Scholar 

  161. Sankar, K. S. et al. Culturing pancreatic islets in microfluidic flow enhances morphology of the associated endothelial cells. PLOS ONE 6, e24904 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  162. Komatsu, H. et al. Oxygen environment and islet size are the primary limiting factors of isolated pancreatic islet survival. PLOS ONE 12, e0183780 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  163. Allazetta, S. & Lutolf, M. P. Stem cell niche engineering through droplet microfluidics. Curr. Opin. Biotechnol. 35, 86–93 (2015).

    CAS  PubMed  Article  Google Scholar 

  164. Bhatia, S. N. & Ingber, D. E. Microfluidic organs-on-chips. Nat. Biotechnol. 32, 760–772 (2014).

    CAS  PubMed  Article  Google Scholar 

  165. Ronaldson-Bouchard, K. & Vunjak-Novakovic, G. Organs-on-a-chip: a fast track for engineered human tissues in drug development. Cell Stem Cell 22, 310–324 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  166. Nguyen, D. T. T., Van Noort, D., Jeong, I. K. & Park, S. Endocrine system on chip for a diabetes treatment model. Biofabrication 9, 015021 (2017).

    PubMed  Article  CAS  Google Scholar 

  167. Ortega-Prieto, A. M. et al. 3D microfluidic liver cultures as a physiological preclinical tool for hepatitis B virus infection. Nat. Commun. 9, 682 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  168. Brandenberg, N. & Lutolf, M. P. In situ patterning of microfluidic networks in 3D cell-laden hydrogels. Adv. Mater. 28, 7450–7456 (2016).

    CAS  PubMed  Article  Google Scholar 

  169. Silva, P. N., Green, B. J., Altamentova, S. M. & Rocheleau, J. V. A microfluidic device designed to induce media flow throughout pancreatic islets while limiting shear-induced damage. Lab. Chip 13, 4374 (2013).

    CAS  PubMed  Article  Google Scholar 

  170. Mohammed, J. S., Wang, Y., Harvat, T. A., Oberholzer, J. & Eddington, D. T. Microfluidic device for multimodal characterization of pancreatic islets. Lab. Chip 9, 97–106 (2009).

    CAS  PubMed  Article  Google Scholar 

  171. Bauer, S. et al. Functional coupling of human pancreatic islets and liver spheroids on-a-chip: towards a novel human ex vivo type 2 diabetes model. Sci. Rep. 7, 14620 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  172. Tritschler, S., Theis, F. J., Lickert, H. & Böttcher, A. Systematic single-cell analysis provides new insights into heterogeneity and plasticity of the pancreas. Mol. Metab. 6, 974–990 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  173. King, A. J. F. The use of animal models in diabetes research. Br. J. Pharmacol. 166, 877–894 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  174. Dufrane, D. et al. Streptozotocin-induced diabetes in large animals (pigs/primates): role of GLUT2 transporter and β-cell plasticity. Transplantation 81, 36–45 (2006).

    CAS  PubMed  Article  Google Scholar 

  175. Kleinert, M. et al. Animal models of obesity and diabetes mellitus. Nat. Rev. Endocrinol. 14, 140–162 (2018).

    PubMed  Article  Google Scholar 

  176. Ionut, V. et al. Novel canine models of obese prediabetes and mild type 2 diabetes. Am. J. Physiol. Endocrinol. Metab. 298, E38–E48 (2010).

    CAS  PubMed  Article  Google Scholar 

  177. Henson, M. S. & O’Brien, T. D. Feline models of type 2 diabetes mellitus. ILAR J. 47, 234–242 (2006).

    CAS  PubMed  Article  Google Scholar 

  178. de Koning, E. J., Bodkin, N. L., Hansen, B. C. & Clark, A. Diabetes mellitus in Macaca mulatta monkeys is characterised by islet amyloidosis and reduction in beta-cell population. Diabetologia 36, 378–384 (1993).

    PubMed  Article  Google Scholar 

  179. Wagner, J. D. et al. Old world nonhuman primate models of type 2 diabetes mellitus. ILAR J. 47, 259–271 (2006).

    CAS  PubMed  Article  Google Scholar 

  180. Renner, S. et al. Metabolic syndrome and extensive adipose tissue inflammation in morbidly obese Göttingen minipigs. Mol. Metab. 16, 180–190 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  181. Bellinger, D. A., Merricks, E. P. & Nichols, T. C. Swine models of type 2 diabetes mellitus: insulin resistance, glucose tolerance, and cardiovascular complications. ILAR J. 47, 243–258 (2006).

    CAS  PubMed  Article  Google Scholar 

  182. Kobayashi, T. et al. Principles of early human development and germ cell program from conserved model systems. Nature 546, 416–420 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  183. Kemter, E. et al. INS-eGFP transgenic pigs: a novel reporter system for studying maturation, growth and vascularisation of neonatal islet-like cell clusters. Diabetologia 60, 1152–1156 (2017).

    CAS  PubMed  Article  Google Scholar 

  184. Umeyama, K. et al. Dominant-negative mutant hepatocyte nuclear factor 1α induces diabetes in transgenic-cloned pigs. Transgen. Res. 18, 697–706 (2009).

    CAS  Article  Google Scholar 

  185. Renner, S. et al. Permanent neonatal diabetes in INSC94Y transgenic pigs. Diabetes 62, 1505–1511 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  186. Ludwig, B. et al. Favorable outcome of experimental islet xenotransplantation without immunosuppression in a nonhuman primate model of diabetes. Proc. Natl Acad. Sci. USA 114, 11745–11750 (2017).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  187. Salama, B. F. & Korbutt, G. S. Porcine islet xenografts: a clinical source of ß-cell grafts. Curr. Diabetes Rep. 17, 14 (2017).

    Article  Google Scholar 

  188. Wu, J. et al. Interspecies chimerism with mammalian pluripotent stem cells. Cell 168, 473–486 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  189. Wu, J. & Belmonte, J. C. I. Interspecies chimeric complementation for the generation of functional human tissues and organs in large animal hosts. Transgen. Res. 25, 375–384 (2016).

    CAS  Article  Google Scholar 

  190. Yamaguchi, T. et al. Interspecies organogenesis generates autologous functional islets. Nature 542, 191–196 (2017).

    CAS  PubMed  Article  Google Scholar 

  191. Matsunari, H. et al. Blastocyst complementation generates exogenic pancreas in vivo in apancreatic cloned pigs. Proc. Natl Acad. Sci. USA 110, 4557–4562 (2013).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  192. Kobayashi, T. et al. Generation of rat pancreas in mouse by interspecific blastocyst injection of pluripotent stem cells. Cell 142, 787–799 (2010).

    CAS  PubMed  Article  Google Scholar 

  193. Korbutt, G. S. et al. Large scale isolation, growth, and function of porcine neonatal islet cells. J. Clin. Invest. 97, 2119–2129 (1996).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  194. Zeng, C. et al. Pseudotemporal ordering of single cells reveals metabolic control of postnatal β cell proliferation. Cell Metab. 25, 1160–1175 (2017). This study uses single-cell RNA sequencing analysis of β-cells at different postnatal stages to reveal metabolic pathways regulating postnatal β-cell proliferation.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  195. Qiu, W. L. et al. Deciphering pancreatic islet β cell and α cell maturation pathways and characteristic features at the single-cell level. Cell Metab. 25, 1194–1205 (2017). This study uses single-cell RNA sequencing analysis of α-cells and β-cells at different postnatal stages to reveal the signalling pathways regulating postnatal β-cell maturation.

    CAS  PubMed  Article  Google Scholar 

  196. Wolf, E., Braun-Reichhart, C., Streckel, E. & Renner, S. Genetically engineered pig models for diabetes research. Transgen. Res. 23, 27–38 (2014).

    CAS  Article  Google Scholar 

  197. Renner, S. et al. Glucose intolerance and reduced proliferation of pancreatic β-cells in transgenic pigs with impaired glucose-dependent insulinotropic polypeptide function. Diabetes 59, 1228–1238 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  198. Liu, M. et al. INS-gene mutations: from genetics and beta cell biology to clinical disease. Mol. Aspects Med. 42, 3–18 (2015).

    CAS  PubMed  Article  Google Scholar 

  199. Szabat, M. et al. Reduced insulin production relieves endoplasmic reticulum stress and induces β cell proliferation. Cell Metab. 23, 179–193 (2016).

    CAS  PubMed  Article  Google Scholar 

  200. O’Sullivan-Murphy, B. & Urano, F. ER stress as a trigger for β-cell dysfunction and autoimmunity in type 1 diabetes. Diabetes 61, 780–781 (2012).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  201. Cui, Y. et al. Fluctuation localization imaging-based fluorescence in situ hybridization (fliFISH) for accurate detection and counting of RNA copies in single cells. Nucleic Acids Res. 46, e7 (2018).

    PubMed  Article  CAS  Google Scholar 

  202. Thiery, G. et al. Multiplex target protein imaging in tissue sections by mass spectrometry - TAMSIM. Rapid Commun. Mass Spectrom. 21, 823–829 (2007).

    CAS  PubMed  Article  Google Scholar 

  203. Kang, C. C. et al. Single cell-resolution western blotting. Nat. Protoc. 11, 1508–1530 (2016).

    PubMed  PubMed Central  Article  Google Scholar 

  204. Wells, J. M. & Melton, D. A. Vertebrate endoderm development. Annu. Rev. Cell Dev. Biol. 15, 393–410 (1999).

    CAS  PubMed  Article  Google Scholar 

  205. Carlsson, G. L., Scott Heller, R., Serup, P. & Hyttel, P. Immunohistochemistry of pancreatic development in cattle and pig. Anat. Histol. Embryol. 39, 107–119 (2010).

    CAS  PubMed  Article  Google Scholar 

  206. Zabel, M. et al. Immunocytochemical studies on endocrine cells of alimentary tract of the pig in the embryonic and fetal period of life. Folia Morphol. (Warsz) 54, 69–80 (1995).

    CAS  Google Scholar 

  207. Alumets, J., Håkanson, R. & Sundler, F. Ontogeny of endocrine cells in porcine gut and pancreas. An immunocytochemical study. Gastroenterology 85, 1359–1372 (1983).

    CAS  PubMed  Article  Google Scholar 

  208. Piper, K. et al. Beta cell differentiation during early human pancreas development. J. Endocrinol. 181, 11–23 (2004).

    CAS  PubMed  Article  Google Scholar 

  209. Kim, A. et al. Islet architecture: a comparative study. Islets 1, 129–136 (2009).

    PubMed  Article  Google Scholar 

  210. Marchetti, P. et al. Morphometrical and immunocytochemical characterization of the porcine endocrine pancreas. Transpl. Proc. 22, 727–728 (1990).

    CAS  Google Scholar 

  211. Orci, L., Malaisse-Lagae, F., Baetens, D. & Perrelet, A. Pancreatic-polypeptide-rich regions in human pancreas. Lancet 312, 1200–1201 (1978).

    Article  Google Scholar 

  212. Bosco, D. et al. Unique arrangement of alpha- and beta-cells in human islets of Langerhans. Diabetes 59, 1202–1210 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

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Acknowledgements

The authors apologize to those whose work has not been cited due to limited space. The authors would like to thank Ciro Salinno for helpful comments on the manuscript. The authors acknowledge the support of the Helmholtz Association (Helmholtz-Gemeinschaft), German Research Foundation (Deutsche Forschungsgemeinschaft) and German Center for Diabetes Research (Deutsches Zentrum für Diabetes Forschung, DZD e.V.).

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Nature Reviews Endocrinology thanks A. Pugliese and the other anonymous reviewers for their contribution to the peer review of this work.

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Juvenile Diabetes Research Foundation (JDRF) network program: www.JDRFnPOD.org

Integrated islet distribution program (IIDP): https://iidp.coh.org

Human islet research network (HIRN): https://hirnetwork.org

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Bakhti, M., Böttcher, A. & Lickert, H. Modelling the endocrine pancreas in health and disease. Nat Rev Endocrinol 15, 155–171 (2019). https://doi.org/10.1038/s41574-018-0132-z

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