Review Article | Published:

Pancreas regeneration

Naturevolume 557pages351358 (2018) | Download Citation


The pancreas is made from two distinct components: the exocrine pancreas, a reservoir of digestive enzymes, and the endocrine islets, the source of the vital metabolic hormone insulin. Human islets possess limited regenerative ability; loss of islet β-cells in diseases such as type 1 diabetes requires therapeutic intervention. The leading strategy for restoration of β-cell mass is through the generation and transplantation of new β-cells derived from human pluripotent stem cells. Other approaches include stimulating endogenous β-cell proliferation, reprogramming non-β-cells to β-like cells, and harvesting islets from genetically engineered animals. Together these approaches form a rich pipeline of therapeutic development for pancreatic regeneration.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Change history

  • 20 June 2018

    Change history: In this Insight Review, ‘1989’ has been changed to ‘1998’ in the sentence “This deep understanding of pancreatic development was put to the service of regenerative medicine in 1998, when human embryonic stem cells (hES cells) were successfully cultured and opened the door to developing methods of deriving pancreatic islets from hES cells66.”. This error has been corrected online.


  1. 1.

    McCarthy, M. I. Genomics, type 2 diabetes, and obesity. N. Engl. J. Med. 363, 2339–2350 (2010).

  2. 2.

    Flannick, J. & Florez, J. C. Type 2 diabetes: genetic data sharing to advance complex disease research. Nat. Rev. Genet. 17, 535–549 (2016).

  3. 3.

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

  4. 4.

    Rahier, J., Guiot, Y., Goebbels, R. M., Sempoux, C. & Henquin, J. C. Pancreatic β-cell mass in European subjects with type 2 diabetes. Diabetes Obes. Metab. 10 (Suppl. 4), 32–42 (2008).

  5. 5.

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

  6. 6.

    Lehv, M. & Fitzgerald, P. J. Pancreatic acinar cell regeneration. IV. Regeneration after resection. Am. J. Pathol. 53, 513–535 (1968).

  7. 7.

    Bonner-Weir, S., Trent, D. F. & Weir, G. C. Partial pancreatectomy in the rat and subsequent defect in glucose-induced insulin release. J. Clin. Invest. 71, 1544–1553 (1983).

  8. 8.

    Watanabe, H., Saito, H., Rychahou, P. G., Uchida, T. & Evers, B. M. Aging is associated with decreased pancreatic acinar cell regeneration and phosphatidylinositol 3-kinase/Akt activation. Gastroenterology 128, 1391–1404 (2005).

  9. 9.

    Kumar, A. F., Gruessner, R. W. & Seaquist, E. R. Risk of glucose intolerance and diabetes in hemipancreatectomized donors selected for normal preoperative glucose metabolism. Diabetes Care 31, 1639–1643 (2008).

  10. 10.

    Menge, B. A. et al. Partial pancreatectomy in adult humans does not provoke β-cell regeneration. Diabetes 57, 142–149 (2008).

  11. 11.

    Berrocal, T., Luque, A. A., Pinilla, I. & Lassaletta, L. Pancreatic regeneration after near-total pancreatectomy in children with nesidioblastosis. Pediatr. Radiol. 35, 1066–1070 (2005).

  12. 12.

    Rankin, M. M. & Kushner, J. A. Adaptive β-cell proliferation is severely restricted with advanced age. Diabetes 58, 1365–1372 (2009).

  13. 13.

    Rankin, M. M. et al. β-Cells are not generated in pancreatic duct ligation-induced injury in adult mice. Diabetes 62, 1634–1645 (2013).

  14. 14.

    Xiao, X. et al. No evidence for β cell neogenesis in murine adult pancreas. J. Clin. Invest. 123, 2207–2217 (2013).

  15. 15.

    Tschen, S. I., Dhawan, S., Gurlo, T. & Bhushan, A. Age-dependent decline in β-cell proliferation restricts the capacity of β-cell regeneration in mice. Diabetes 58, 1312–1320 (2009).

  16. 16.

    Mezza, T. & Kulkarni, R. N. The regulation of pre- and post-maturational plasticity of mammalian islet cell mass. Diabetologia 57, 1291–1303 (2014).

  17. 17.

    Saunders, D. & Powers, A. C. Replicative capacity of β-cells and type 1 diabetes. J. Autoimmun. 71, 59–68 (2016).

  18. 18.

    Wang, P. et al. Diabetes mellitus—advances and challenges in human β-cell proliferation. Nat. Rev. Endocrinol. 11, 201–212 (2015).

  19. 19.

    Rieck, S. & Kaestner, K. H. Expansion of β-cell mass in response to pregnancy. Trends Endocrinol. Metab. 21, 151–158 (2010).

  20. 20.

    Ernst, S., Demirci, C., Valle, S., Velazquez-Garcia, S. & Garcia-Ocaña, A. Mechanisms in the adaptation of maternal β-cells during pregnancy. Diabetes Manag. (Lond.) 1, 239–248 (2011).

  21. 21.

    Kim, H. et al. Serotonin regulates pancreatic β-cell mass during pregnancy. Nat. Med. 16, 804–808 (2010).

  22. 22.

    Zhang, H. et al. Gestational diabetes mellitus resulting from impaired β-cell compensation in the absence of FoxM1, a novel downstream effector of placental lactogen. Diabetes 59, 143–152 (2010).

  23. 23.

    Karnik, S. K. et al. Menin controls growth of pancreatic β-cells in pregnant mice and promotes gestational diabetes mellitus. Science 318, 806–809 (2007).

  24. 24.

    Kahn, S. E., Hull, R. L. & Utzschneider, K. M. Mechanisms linking obesity to insulin resistance and type 2 diabetes. Nature 444, 840–846 (2006).

  25. 25.

    Michael, M. D. et al. Loss of insulin signaling in hepatocytes leads to severe insulin resistance and progressive hepatic dysfunction. Mol. Cell 6, 87–97 (2000).

  26. 26.

    Finegood, D. T., Scaglia, L. & Bonner-Weir, S. Dynamics of β-cell mass in the growing rat pancreas. Estimation with a simple mathematical model. Diabetes 44, 249–256 (1995).

  27. 27.

    Teta, M., Long, S. Y., Wartschow, L. M., Rankin, M. M. & Kushner, J. A. Very slow turnover of β-cells in aged adult mice. Diabetes 54, 2557–2567 (2005).

  28. 28.

    Montanya, E., Nacher, V., Biarnés, M. & Soler, J. Linear correlation between beta-cell mass and body weight throughout the lifespan in Lewis rats: role of β-cell hyperplasia and hypertrophy. Diabetes 49, 1341–1346 (2000).

  29. 29.

    Dor, Y., Brown, J., Martinez, O. I. & Melton, D. A. Adult pancreatic β-cells are formed by self-duplication rather than stem-cell differentiation. Nature 429, 41–46 (2004). This paper used genetic lineage tracing in mouse models and convincingly demonstrated β-cell replication as a major mechanism for maintaining β-cell mass in homeostasis.

  30. 30.

    Saisho, Y. et al. β-cell mass and turnover in humans: effects of obesity and aging. Diabetes Care 36, 111–117 (2013).

  31. 31.

    Butler, A. E. et al. Adaptive changes in pancreatic β cell fractional area and β cell turnover in human pregnancy. Diabetologia 53, 2167–2176 (2010).

  32. 32.

    Thorel, F. et al. Conversion of adult pancreatic α-cells to β-cells after extreme β-cell loss. Nature 464, 1149–1154 (2010). Data from this paper suggested that mouse pancreatic α-cells could naturally convert to β-cells after extreme β-cell loss.

  33. 33.

    Chera, S. et al. Diabetes recovery by age-dependent conversion of pancreatic δ-cells into insulin producers. Nature 514, 503–507 (2014).

  34. 34.

    Aguayo-Mazzucato, C. & Bonner-Weir, S. Pancreatic β cell regeneration as a possible therapy for diabetes. Cell Metab. 27, 57–67 (2018).

  35. 35.

    Desai, B. M. et al. Preexisting pancreatic acinar cells contribute to acinar cell, but not islet β cell, regeneration. J. Clin. Invest. 117, 971–977 (2007).

  36. 36.

    Kopp, J. L. et al. Sox9+ ductal cells are multipotent progenitors throughout development but do not produce new endocrine cells in the normal or injured adult pancreas. Development 138, 653–665 (2011).

  37. 37.

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

  38. 38.

    Pan, F. C. et al. Spatiotemporal patterns of multipotentiality in Ptf1a-expressing cells during pancreas organogenesis and injury-induced facultative restoration. Development 140, 751–764 (2013).

  39. 39.

    Kopinke, D. & Murtaugh, L. C. Exocrine-to-endocrine differentiation is detectable only prior to birth in the uninjured mouse pancreas. BMC Dev. Biol. 10, 38 (2010).

  40. 40.

    Xu, X. et al. β cells can be generated from endogenous progenitors in injured adult mouse pancreas. Cell 132, 197–207 (2008).

  41. 41.

    Al-Hasani, K. et al. Adult duct-lining cells can reprogram into β-like cells able to counter repeated cycles of toxin-induced diabetes. Dev. Cell 26, 86–100 (2013).

  42. 42.

    Ben-Othman, N. et al. Long-term GABA administration induces α-cell-mediated β-like cell neogenesis. Cell 168, 73–85 (2017).

  43. 43.

    Lowenfels, A. B., Sullivan, T., Fiorianti, J. & Maisonneuve, P. The epidemiology and impact of pancreatic diseases in the United States. Curr. Gastroenterol. Rep. 7, 90–95 (2005).

  44. 44.

    Willemer, S., Elsässer, H. P. & Adler, G. Hormone-induced pancreatitis. Eur. Surg. Res. 24 (Suppl. 1), 29–39 (1992).

  45. 45.

    Lerch, M. M. & Gorelick, F. S. Models of acute and chronic pancreatitis. Gastroenterology 144, 1180–1193 (2013).

  46. 46.

    Bockman, D. E. Morphology of the exocrine pancreas related to pancreatitis. Microsc. Res. Tech. 37, 509–519 (1997).

  47. 47.

    Bockman, D. E., Boydston, W. R. & Anderson, M. C. Origin of tubular complexes in human chronic pancreatitis. Am. J. Surg. 144, 243–249 (1982).

  48. 48.

    Willemer, S. & Adler, G. Histochemical and ultrastructural characteristics of tubular complexes in human acute pancreatitis. Dig. Dis. Sci. 34, 46–55 (1989).

  49. 49.

    Murtaugh, L. C. & Keefe, M. D. Regeneration and repair of the exocrine pancreas. Annu. Rev. Physiol. 77, 229–249 (2015).

  50. 50.

    Blaine, S. A. et al. Adult pancreatic acinar cells give rise to ducts but not endocrine cells in response to growth factor signaling. Development 137, 2289–2296 (2010).

  51. 51.

    Strobel, O. et al. In vivo lineage tracing defines the role of acinar-to-ductal transdifferentiation in inflammatory ductal metaplasia. Gastroenterology 133, 1999–2009 (2007).

  52. 52.

    Morris, J. P. IV, Cano, D. A., Sekine, S., Wang, S. C. & Hebrok, M. β-catenin blocks Kras-dependent reprogramming of acini into pancreatic cancer precursor lesions in mice. J. Clin. Invest. 120, 508–520 (2010).

  53. 53.

    Fendrich, V. et al. Hedgehog signaling is required for effective regeneration of exocrine pancreas. Gastroenterology 135, 621–631 (2008).

  54. 54.

    Siveke, J. T. et al. Notch signaling is required for exocrine regeneration after acute pancreatitis. Gastroenterology 134, 544–555 (2008).

  55. 55.

    Hoang, C. Q. et al. Transcriptional maintenance of pancreatic acinar identity, differentiation, and homeostasis by PTF1A. Mol. Cell. Biol. 36, 3033–3047 (2016).

  56. 56.

    von Figura, G., Morris, J. P. IV, Wright, C. V. & Hebrok, M. Nr5a2 maintains acinar cell differentiation and constrains oncogenic Kras-mediated pancreatic neoplastic initiation. Gut 63, 656–664 (2014).

  57. 57.

    Kopp, J. L. et al. Identification of Sox9-dependent acinar-to-ductal reprogramming as the principal mechanism for initiation of pancreatic ductal adenocarcinoma. Cancer Cell 22, 737–750 (2012).

  58. 58.

    Stanger, B. Z. & Hebrok, M. Control of cell identity in pancreas development and regeneration. Gastroenterology 144, 1170–1179 (2013).

  59. 59.

    Bluestone, J. A., Herold, K. & Eisenbarth, G. Genetics, pathogenesis and clinical interventions in type 1 diabetes. Nature 464, 1293–1300 (2010).

  60. 60.

    Atkinson, M. A. et al. How does type 1 diabetes develop? The notion of homicide or β-cell suicide revisited. Diabetes 60, 1370–1379 (2011).

  61. 61.

    Lakey, J. R., Mirbolooki, M. & Shapiro, A. M. Current status of clinical islet cell transplantation. Methods Mol. Biol. 333, 47–104 (2006).

  62. 62.

    Hering, B. J. et al. Phase 3 trial of transplantation of human islets in type 1 diabetes complicated by severe hypoglycemia. Diabetes Care 39, 1230–1240 (2016).

  63. 63.

    Arda, H. E., Benitez, C. M. & Kim, S. K. Gene regulatory networks governing pancreas development. Dev. Cell 25, 5–13 (2013).

  64. 64.

    McCracken, K. W. & Wells, J. M. Molecular pathways controlling pancreas induction. Semin. Cell Dev. Biol. 23, 656–662 (2012).

  65. 65.

    Murtaugh, L. C. & Melton, D. A. Genes, signals, and lineages in pancreas development. Annu. Rev. Cell Dev. Biol. 19, 71–89 (2003).

  66. 66.

    Thomson, J. A. et al. Embryonic stem cell lines derived from human blastocysts. Science 282, 1145–1147 (1998).

  67. 67.

    Takahashi, K. et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131, 861–872 (2007).

  68. 68.

    D’Amour, K. A. et al. Production of pancreatic hormone-expressing endocrine cells from human embryonic stem cells. Nat. Biotechnol. 24, 1392–1401 (2006). Refs 68 and 69 were among the first to report differentiation of hES cells toward pancreatic endocrine progenitors and islet cells.

  69. 69.

    Kroon, E. et al. Pancreatic endoderm derived from human embryonic stem cells generates glucose-responsive insulin-secreting cells in vivo. Nat. Biotechnol. 26, 443–452 (2008).

  70. 70.

    Pagliuca, F. W. et al. Generation of functional human pancreatic β cells in vitro. Cell 159, 428–439 (2014). Refs 70 and 71 reported successful generation of glucose-sensitive islet clusters by in vitro differentiation of hES and iPS cells.

  71. 71.

    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).

  72. 72.

    Szot, G. L. et al. Tolerance induction and reversal of diabetes in mice transplanted with human embryonic stem cell-derived pancreatic endoderm. Cell Stem Cell 16, 148–157 (2015).

  73. 73.

    Andersson, O. et al. Adenosine signaling promotes regeneration of pancreatic β cells in vivo. Cell Metab. 15, 885–894 (2012).

  74. 74.

    Schulz, N. et al. Critical role for adenosine receptor A2a in β-cell proliferation. Mol. Metab. 5, 1138–1146 (2016).

  75. 75.

    Annes, J. P. et al. Adenosine kinase inhibition selectively promotes rodent and porcine islet β-cell replication. Proc. Natl Acad. Sci. USA 109, 3915–3920 (2012).

  76. 76.

    Kassem, S. A., Ariel, I., Thornton, P. S., Scheimberg, I. & Glaser, B. Beta-cell proliferation and apoptosis in the developing normal human pancreas and in hyperinsulinism of infancy. Diabetes 49, 1325–1333 (2000).

  77. 77.

    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).

  78. 78.

    Köhler, C. U. et al. Cell cycle control of β-cell replication in the prenatal and postnatal human pancreas. Am. J. Physiol. Endocrinol. Metab. 300, E221–E230 (2011).

  79. 79.

    Gregg, B. E. et al. Formation of a human β-cell population within pancreatic islets is set early in life. J. Clin. Endocrinol. Metab. 97, 3197–3206 (2012).

  80. 80.

    Dai, C. et al. Islet-enriched gene expression and glucose-induced insulin secretion in human and mouse islets. Diabetologia 55, 707–718 (2012).

  81. 81.

    De Vos, A. et al. Human and rat β cells differ in glucose transporter but not in glucokinase gene expression. J. Clin. Invest. 96, 2489–2495 (1995).

  82. 82.

    Ferrer, J., Benito, C. & Gomis, R. Pancreatic islet GLUT2 glucose transporter mRNA and protein expression in humans with and without NIDDM. Diabetes 44, 1369–1374 (1995).

  83. 83.

    Kulkarni, R. N., Mizrachi, E. B., Ocana, A. G. & Stewart, A. F. Human β-cell proliferation and intracellular signaling: driving in the dark without a road map. Diabetes 61, 2205–2213 (2012).

  84. 84.

    Bernal-Mizrachi, E. et al. Human β-cell proliferation and intracellular signaling part 2: still driving in the dark without a road map. Diabetes 63, 819–831 (2014).

  85. 85.

    Stewart, A. F. et al. Human β-cell proliferation and intracellular signaling: part 3. Diabetes 64, 1872–1885 (2015).

  86. 86.

    Fiaschi-Taesch, N. M. et al. Human pancreatic β-cell G1/S molecule cell cycle atlas. Diabetes 62, 2450–2459 (2013).

  87. 87.

    Fiaschi-Taesch, N. M. et al. Cytoplasmic-nuclear trafficking of G1/S cell cycle molecules and adult human β-cell replication: a revised model of human β-cell G1/S control. Diabetes 62, 2460–2470 (2013).

  88. 88.

    Krishnamurthy, J. et al. p16INK4a induces an age-dependent decline in islet regenerative potential. Nature 443, 453–457 (2006).

  89. 89.

    Chen, H. et al. Polycomb protein Ezh2 regulates pancreatic β-cell Ink4a/Arf expression and regeneration in diabetes mellitus. Genes Dev. 23, 975–985 (2009).

  90. 90.

    Helman, A. et al. p16Ink4a-induced senescence of pancreatic beta cells enhances insulin secretion. Nat. Med. 22, 412–420 (2016).

  91. 91.

    Kulkarni, R. N. New insights into the roles of insulin/IGF-I in the development and maintenance of β-cell mass. Rev. Endocr. Metab. Disord. 6, 199–210 (2005).

  92. 92.

    Dadon, D. et al. Glucose metabolism: key endogenous regulator of β-cell replication and survival. Diabetes Obes. Metab. 14 (Suppl 3), 101–108 (2012).

  93. 93.

    Stamateris, R. E. et al. Glucose induces mouse β-cell proliferation via IRS2, MTOR, and cyclin D2 but not the insulin receptor. Diabetes 65, 981–995 (2016).

  94. 94.

    Wang, P. et al. A high-throughput chemical screen reveals that harmine-mediated inhibition of DYRK1A increases human pancreatic β cell replication. Nat. Med. 21, 383–388 (2015). Refs 94, 95 and 96 identified DRYK1 inhibitors as reagents that stimulate human β-cell proliferation.

  95. 95.

    Dirice, E. et al. Inhibition of DYRK1A stimulates human β-cell proliferation. Diabetes 65, 1660–1671 (2016).

  96. 96.

    Shen, W. et al. Inhibition of DYRK1A and GSK3B induces human β-cell proliferation. Nat. Commun. 6, 8372 (2015).

  97. 97.

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

  98. 98.

    Dai, C. et al. Age-dependent human β cell proliferation induced by glucagon-like peptide 1 and calcineurin signaling. J. Clin. Invest. 127, 3835–3844 (2017).

  99. 99.

    Slack, J. M. Metaplasia and transdifferentiation: from pure biology to the clinic. Nat. Rev. Mol. Cell Biol. 8, 369–378 (2007).

  100. 100.

    Eguchi, G. & Okada, T. S. Differentiation of lens tissue from the progeny of chick retinal pigment cells cultured in vitro: a demonstration of a switch of cell types in clonal cell culture. Proc. Natl Acad. Sci. USA 70, 1495–1499 (1973).

  101. 101.

    Choi, J. et al. MyoD converts primary dermal fibroblasts, chondroblasts, smooth muscle, and retinal pigmented epithelial cells into striated mononucleated myoblasts and multinucleated myotubes. Proc. Natl Acad. Sci. USA 87, 7988–7992 (1990).

  102. 102.

    Gurdon, J. B. From nuclear transfer to nuclear reprogramming: the reversal of cell differentiation. Annu. Rev. Cell Dev. Biol. 22, 1–22 (2006).

  103. 103.

    Ferber, S. et al. Pancreatic and duodenal homeobox gene 1 induces expression of insulin genes in liver and ameliorates streptozotocin-induced hyperglycemia. Nat. Med. 6, 568–572 (2000).

  104. 104.

    Heremans, Y. et al. Recapitulation of embryonic neuroendocrine differentiation in adult human pancreatic duct cells expressing neurogenin 3. J. Cell Biol. 159, 303–312 (2002).

  105. 105.

    Gasa, R. et al. Proendocrine genes coordinate the pancreatic islet differentiation program in vitro. Proc. Natl Acad. Sci. USA 101, 13245–13250 (2004).

  106. 106.

    Kaneto, H. et al. PDX-1/VP16 fusion protein, together with NeuroD or Ngn3, markedly induces insulin gene transcription and ameliorates glucose tolerance. Diabetes 54, 1009–1022 (2005).

  107. 107.

    Minami, K., Okano, H., Okumachi, A. & Seino, S. Role of cadherin-mediated cell–cell adhesion in pancreatic exocrine-to-endocrine transdifferentiation. J. Biol. Chem. 283, 13753–13761 (2008).

  108. 108.

    Baeyens, L. et al. In vitro generation of insulin-producing β cells from adult exocrine pancreatic cells. Diabetologia 48, 49–57 (2005).

  109. 109.

    Zhou, Q., Brown, J., Kanarek, A., Rajagopal, J. & Melton, D. A. In vivo reprogramming of adult pancreatic exocrine cells to β-cells. Nature 455, 627–632 (2008). This paper showed that it is possible to directly convert pancreatic acinar cells to β-like cells in adult mice.

  110. 110.

    Li, W. et al. Long-term persistence and development of induced pancreatic β cells generated by lineage conversion of acinar cells. Nat. Biotechnol. 32, 1223–1230 (2014).

  111. 111.

    Chen, Y. J. et al. De novo formation of insulin-producing “neo-β cell islets” from intestinal crypts. Cell Reports 6, 1046–1058 (2014).

  112. 112.

    Ariyachet, C. et al. Reprogrammed stomach tissue as a renewable source of functional β cells for blood glucose regulation. Cell Stem Cell 18, 410–421 (2016).

  113. 113.

    Talchai, C., Xuan, S., Kitamura, T., DePinho, R. A. & Accili, D. Generation of functional insulin-producing cells in the gut by Foxo1 ablation. Nat Genet. 44, 406–412 (2012).

  114. 114.

    Baeyens, L. et al. Transient cytokine treatment induces acinar cell reprogramming and regenerates functional beta cell mass in diabetic mice. Nat. Biotechnol. 32, 76–83 (2014).

  115. 115.

    Sancho, R., Gruber, R., Gu, G. & Behrens, A. Loss of Fbw7 reprograms adult pancreatic ductal cells into α, δ, and β cells. Cell Stem Cell 15, 139–153 (2014).

  116. 116.

    Cerdá-Esteban, N. et al. Stepwise reprogramming of liver cells to a pancreas progenitor state by the transcriptional regulator Tgif2. Nat. Commun. 8, 14127 (2017).

  117. 117.

    Courtney, M. et al. The inactivation of Arx in pancreatic α-cells triggers their neogenesis and conversion into functional β-like cells. PLoS Genet. 9, e1003934 (2013).

  118. 118.

    Collombat, P. et al. The ectopic expression of Pax4 in the mouse pancreas converts progenitor cells into α and subsequently β cells. Cell 138, 449–462 (2009).

  119. 119.

    van der Meulen, T. et al. Virgin β cells persist throughout life at a neogenic niche within pancreatic islets. Cell Metab. 25, 911–926 (2017).

  120. 120.

    Xiao, X. et al. Endogenous reprogramming of α cells into β cells, induced by viral gene therapy, reverses autoimmune diabetes. Cell Stem Cell 22, 78–90 (2018).

  121. 121.

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

  122. 122.

    Bouchi, R. et al. FOXO1 inhibition yields functional insulin-producing cells in human gut organoid cultures. Nat. Commun. 5, 4242 (2014).

  123. 123.

    Galivo, F. et al. Reprogramming human gallbladder cells into insulin-producing β-like cells. PLoS ONE  12, e0181812 (2017).

  124. 124.

    Lemper, M. et al. Reprogramming of human pancreatic exocrine cells to β-like cells. Cell Death Differ. 22, 1117–1130 (2015).

  125. 125.

    Sun, Y., Ma, X., Zhou, D., Vacek, I. & Sun, A. M. Normalization of diabetes in spontaneously diabetic cynomologus monkeys by xenografts of microencapsulated porcine islets without immunosuppression. J. Clin. Invest. 98, 1417–1422 (1996).

  126. 126.

    Dufrane, D., Goebbels, R. M., Saliez, A., Guiot, Y. & Gianello, P. Six-month survival of microencapsulated pig islets and alginate biocompatibility in primates: proof of concept. Transplantation 81, 1345–1353 (2006).

  127. 127.

    Elliott, R. B. Towards xenotransplantation of pig islets in the clinic. Curr. Opin. Organ Transplant. 16, 195–200 (2011).

  128. 128.

    Niu, D. et al. Inactivation of porcine endogenous retrovirus in pigs using CRISPR–Cas9. Science 357, 1303–1307 (2017).

  129. 129.

    Yang, L. et al. Genome-wide inactivation of porcine endogenous retroviruses (PERVs). Science 350, 1101–1104 (2015).

  130. 130.

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

  131. 131.

    Rashid, T., Kobayashi, T. & Nakauchi, H. Revisiting the flight of Icarus: making human organs from PSCs with large animal chimeras. Cell Stem Cell 15, 406–409 (2014).

  132. 132.

    Yamaguchi, T. et al. Interspecies organogenesis generates autologous functional islets. Nature 542, 191–196 (2017). This paper demonstrated the feasibility of harvesting interspecies-derived islets to control diabetes with rodent models.

  133. 133.

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

  134. 134.

    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). This paper suggested that dedifferentiation is a potential major mechanism for β-cell failure in T2D.

  135. 135.

    Accili, D. et al. When β-cells fail: lessons from dedifferentiation. Diabetes Obes. Metab. 18 (Suppl. 1), 117–122 (2016).

  136. 136.

    Orlando, G. et al. Cell replacement strategies aimed at reconstitution of the β-cell compartment in type 1 diabetes. Diabetes 63, 1433–1444 (2014).

  137. 137.

    Vegas, A. J. et al. Long-term glycemic control using polymer-encapsulated human stem cell-derived β cells in immune-competent mice. Nat. Med. 22, 306–311 (2016).

  138. 138.

    An, D. et al. Designing a retrievable and scalable cell encapsulation device for potential treatment of type 1 diabetes. Proc. Natl Acad. Sci. USA 115, E263–E272 (2018).

  139. 139.

    Manzoli, V. et al. Immunoisolation of murine islet allografts in vascularized sites through conformal coating with polyethylene glycol. Am. J. Transplant. 18, 590–603 (2018).

  140. 140.

    Chen, T. et al. Alginate encapsulant incorporating CXCL12 supports long-term allo- and xenoislet transplantation without systemic immune suppression. Am. J. Transplant. 15, 618–627 (2015).

  141. 141.

    Shoda, L. K. et al. A comprehensive review of interventions in the NOD mouse and implications for translation. Immunity 23, 115–126 (2005).

  142. 142.

    Lernmark, A. & Larsson, H. E. Immune therapy in type 1 diabetes mellitus. Nat. Rev. Endocrinol. 9, 92–103 (2013).

  143. 143.

    Reed, J. C. & Herold, K. C. Thinking bedside at the bench: the NOD mouse model of T1DM. Nat. Rev. Endocrinol. 11, 308–314 (2015).

  144. 144.

    Keenan, H. A. et al. Residual insulin production and pancreatic β-cell turnover after 50 years of diabetes: Joslin Medalist Study. Diabetes 59, 2846–2853 (2010). This paper demonstrated the persistence of insulin-expressing cells in patients with long-term T1D.

  145. 145.

    Liu, E. H. et al. Pancreatic β cell function persists in many patients with chronic type 1 diabetes, but is not dramatically improved by prolonged immunosuppression and euglycaemia from a β cell allograft. Diabetologia 52, 1369–1380 (2009).

  146. 146.

    Dorrell, C. et al. Human islets contain four distinct subtypes of β cells. Nat. Commun. 7, 11756 (2016). Refs 146 and 147 suggested that islet β-cells are heterogeneous in their molecular and functional properties.

  147. 147.

    Bader, E. et al. Identification of proliferative and mature β-cells in the islets of Langerhans. Nature 535, 430–434 (2016).

  148. 148.

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

  149. 149.

    Johnston, N. R. et al. β Cell hubs dictate pancreatic islet responses to glucose. Cell Metab. 24, 389–401 (2016).

Download references


We apologize that we were unable to cite many studies owing to space limitations. We thank past and present members of our laboratories and colleagues for their insights and contributions. Q.Z. and D.A.M. receive support from National Institute of Health (NIH) and Harvard Stem Cell Institute (HSCI), and D.A.M. from Howard Hughes Medical Institute (HHMI).

Author information


  1. Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA

    • Qiao Zhou
    •  & Douglas A. Melton
  2. Harvard Stem Cell Institute, Cambridge, MA, USA

    • Qiao Zhou
    •  & Douglas A. Melton
  3. Howard Hughes Medical Institute, Chevy Chase, MD, USA

    • Douglas A. Melton


  1. Search for Qiao Zhou in:

  2. Search for Douglas A. Melton in:


Q.Z. and D.A.M. wrote and edited the manuscript. Q.Z. prepared the figures.

Competing interests

D.A.M. is a founder of Semma Therapeutics Inc. Q.Z. declares no competing interests.

Corresponding authors

Correspondence to Qiao Zhou or Douglas A. Melton.

About this article

Publication history




Issue Date


Further reading


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.