Human Beta Cells Generated from Pluripotent Stem Cells or Cellular Reprogramming for Curing Diabetes

  • Lauren N. Randolph
  • Agamoni Bhattacharyya
  • Xiaojun Lance LianEmail author


Diabetes is a group of metabolic diseases characterized by aberrantly high blood glucose levels caused by defects in insulin secretion or its action, or both, which affects approximately 30.3 million people (9.4% of the population) in the USA. This review will focus on using human β cells to treat and cure diabetes because β cells are absent, due to an autoimmune destruction, in type 1 diabetes or dysfunctional in type 2 diabetes. In order to generate enough functional β cells for diabetes treatment (0.1 to 1 billion cells to treat one patient), a basic science approach by mimicking what happens in normal pancreatic development must be closely aligned with engineering. Two general approaches are discussed here. The first one uses human pluripotent stem cells (hPSCs) to perform directed differentiation of hPSCs to β cells. This is advantageous because hPSCs grow indefinitely, providing a virtually unlimited source of material. Therefore, if we develop an efficient β cell differentiation protocol, we can essentially generate an unlimited amount of β cells for disease modeling and diabetes treatment. The second approach is cellular reprogramming, with which we may begin with any cell type and convert it directly into a β cell. The success of this cellular reprogramming approach, however, depends on the discovery of a robust and efficient transcription factor cocktail that can ignite this process, similar to what has been achieved in generating induced pluripotent stem cells. This discovery should be possible through identifying the important transcription factors and pioneer factors via recent advances in single-cell RNA sequencing. In short, a new renaissance in pancreas developmental biology, stem cell engineering, and cellular reprogramming for curing diabetes appears to be on the horizon.

Lay Summary

The prevalence of type 1 diabetes is slowly increasing worldwide. It is an autoimmune disease that destroys pancreatic β cells, which are responsible for producing insulin to regulate blood glucose levels in the body. To overcome this deficiency in insulin-producing cells, scientists and researchers have been trying to generate functional β cells from either human pluripotent stem cells, using directed differentiation, or from other somatic cell types, using cellular reprogramming. Here, we discuss the various techniques that have been developed and implemented, both in vitro and in vivo, in the last 20 years. Current methods have some drawbacks, including low efficiency of generating functional β cells after differentiation or reprogramming. Therefore, future works in this field must include increasing the efficiency of functional β cell production, implementing the use of low-cost materials, and testing these methods in diabetic primates and humans.


Human pluripotent stem cells Beta cells Directed differentiation Cellular reprogramming Type 1 diabetes 


  1. 1.
    Thomson JA, Itskovitz-Eldor J, Shapiro SS, Waknitz MA, Swiergiel JJ, Marshall VS, et al. Embryonic stem cell lines derived from human blastocysts. Science. 1998;282:1145–7.CrossRefGoogle Scholar
  2. 2.
    Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell. 2006;126:663–76.CrossRefGoogle Scholar
  3. 3.
    Yamanaka S, et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell. 2007;131:861–72.CrossRefGoogle Scholar
  4. 4.
    Yu J, et al. Induced pluripotent stem cell lines derived from human somatic cells. Science. 2007;318:1917–20.CrossRefGoogle Scholar
  5. 5.
    Lian X, Hsiao C, Wilson G, Zhu K, Hazeltine LB, Azarin SM, et al. Robust cardiomyocyte differentiation from human pluripotent stem cells via temporal modulation of canonical Wnt signaling. Proc Natl Acad Sci. 2012;109:E1848–57.Google Scholar
  6. 6.
    Lian X, Bao X, Zilberter M, Westman M, Fisahn A, Hsiao C, et al. Chemically defined, albumin-free human cardiomyocyte generation. Nat Methods. 2015;12:595–6.CrossRefGoogle Scholar
  7. 7.
    Lian X, Zhang J, Azarin SM, Zhu K, Hazeltine LB, Bao X, et al. Directed cardiomyocyte differentiation from human pluripotent stem cells by modulating Wnt/β-catenin signaling under fully defined conditions. Nat Protoc. 2013;8:162–75.CrossRefGoogle Scholar
  8. 8.
    Benitez CM, Goodyer WR, Kim SK. Deconstructing pancreas developmental biology. Cold Spring Harb Perspect Biol. 2012;4:1–17.CrossRefGoogle Scholar
  9. 9.
    Dunning BE, Foley JE, Ahren B. Alpha cell function in health and disease: influence of glucagon-like peptide-1. Diabetologia. 2005;48:1700–13.CrossRefGoogle Scholar
  10. 10.
    Hauge-evans AC, et al. Somatostatin secreted by islet δ-cells fulfills multiple roles as a paracrine regulator of islet function. Diabetes. 2009;58:403–11.CrossRefGoogle Scholar
  11. 11.
    Batterham RL, le Roux CW, Cohen MA, Park AJ, Ellis SM, Patterson M, et al. Pancreatic polypeptide reduces appetite and food intake in humans. J Clin Endocrinol Metab. 2003;88:3989–92.CrossRefGoogle Scholar
  12. 12.
    Dickson SL, et al. The role of the central ghrelin system in reward from food and chemical drugs. Mol Cell Endocrinol. 2011;340:80–7.CrossRefGoogle Scholar
  13. 13.
    Hou JC, Min L, Pessin JE. Insulin granule biogenesis, trafficking and exocytosis. Vitam Horm. 2009:478–506.
  14. 14.
    Yoon J-W, Jun H-S. Autoimmune destruction of pancreatic β cells. Am J Ther. 2005;591:580–91.Google Scholar
  15. 15.
    Borchers AT, Uibo R, Gershwin ME. Autoimmunity reviews the geoepidemiology of type 1 diabetes. Autoimmun Rev. 2018;9:A355–65.CrossRefGoogle Scholar
  16. 16.
    Sander M, German MS. The beta cell transcription factors and development of the pancreas. J Mol Med (Berl). 1997;75:327–40.CrossRefGoogle Scholar
  17. 17.
    Landsberg L, Molitch M. Diabetes and hypertension: pathogenesis, prevention and treatment. Clin Exp Hypertens. 2004;26:621–8.CrossRefGoogle Scholar
  18. 18.
    Tao B, Pietropaolo M, Atkinson M, Schatz D, Taylor D. Estimating the cost of type 1 diabetes in the U.S: a propensity score matching method. PLoS One. 2010;5:11501.CrossRefGoogle Scholar
  19. 19.
    Pan FC, Wright C. Pancreas organogenesis: from bud to plexus to gland. Dev Dyn. 2011;240:530–65.CrossRefGoogle Scholar
  20. 20.
    Dhanantwari P, Lee E, Krishnan A, Samtani R, Yamada S, Anderson S, et al. Human cardiac development in the first trimester a high-resolution magnetic resonance imaging and episcopic fluorescence image capture atlas. Circulation. 2009;120:343–51. Scholar
  21. 21.
    Pagliuca FW, Melton DA. How to make a functional beta cell. Development. 2013;140:2472–83.CrossRefGoogle Scholar
  22. 22.
    Gannon M, Herrera P, Wright CVE. Mosaic Cre-mediated recombination in pancreas using the pdx-1 enhancer / promoter. Genesis. 2000;144:143–4.CrossRefGoogle Scholar
  23. 23.
    Kim SK, Melton DA. Pancreas development is promoted by cyclopamine, a Hedgehog signaling inhibitor. Proc Natl Acad Sci. 1998;95:13036–41.CrossRefGoogle Scholar
  24. 24.
    Molotkov A, Molotkova N, Duester G. Retinoic acid generated by Raldh2 in mesoderm is required for mouse dorsal endodermal pancreas development. Dev Dyn. 2005;232:950–7. Scholar
  25. 25.
    Apelqvist A, Li H, Sommer L, Beatus P, Anderson DJ, Honjo T, et al. Notch signalling controls pancreatic cell differentiation. Nature. 1999;400:877–81.CrossRefGoogle Scholar
  26. 26.
    Lumelsky N, et al. Differentiation of embryonic stem cells to insulin-secreting structures similar to pancreatic islets. Science. 2001;292:1389–94.CrossRefGoogle Scholar
  27. 27.
    Otonkoski T, Beattie GM, Mally MI, Ricordi C, Hayek A. Nicotinamide is a potent inducer of endocrine differentiation in cultured human fetal pancreatic cells. J Clin Invest. 1993;92:1459–66.CrossRefGoogle Scholar
  28. 28.
    Cogger KF, Sinha A, Sarangi F, McGaugh EC, Saunders D, Dorrell C, et al. Glycoprotein 2 is a specific cell surface marker of human pancreatic progenitors. Nat Commun. 2017;8:331.
  29. 29.
    D’Amour KA, et al. Efficient differentiation of human embryonic stem cells to definitive endoderm. Nat Biotechnol. 2005;23:1534–41.CrossRefGoogle Scholar
  30. 30.
    D’Amour KA, et al. Production of pancreatic hormone-expressing endocrine cells from human embryonic stem cells. Nat Biotechnol. 2006;24:1392–401.CrossRefGoogle Scholar
  31. 31.
    Kroon E, et al. Pancreatic endoderm derived from human embryonic stem cells generates glucose-responsive insulin-secreting cells in vivo. Nat Biotechnol. 2008;26:443–52.CrossRefGoogle Scholar
  32. 32.
    Jiang J, et al. Generation of insulin-producing islet-like clusters from human embryonic stem cells. Stem Cells. 2007;25:1940–53.CrossRefGoogle Scholar
  33. 33.
    Nostro MC, Sarangi F, Ogawa S, Holtzinger A, Corneo B, Li X, et al. Stage-specific signaling through TGFβ family members and WNT regulates patterning and pancreatic specification of human pluripotent stem cells. Development. 2011;138:861–71.CrossRefGoogle Scholar
  34. 34.
    Inman GJ, Nicolás FJ, Callahan JF, Harling JD, Gaster LM, Reith AD, et al. SB-431542 is a potent and specific inhibitor of transforming growth factor-β superfamily type I activin receptor-like kinase (ALK) receptors ALK4, ALK5, and ALK7. Mol Pharmacol. 2002;62:65–74.CrossRefGoogle Scholar
  35. 35.
    Nostro MC, Sarangi F, Yang C, Holland A, Elefanty AG, Stanley EG, et al. Efficient generation of NKX6-1+ pancreatic progenitors from multiple human pluripotent stem cell lines. Stem Cell Rep. 2015;4:591–604.CrossRefGoogle Scholar
  36. 36.
    Herrera PL. Adult insulin- and glucagon-producing cells differentiate from two independent cell lineages. Development. 2000;2322:2317–22.Google Scholar
  37. 37.
    Rezania A, et al. Reversal of diabetes with insulin-producing cells derived in vitro from human pluripotent stem cells. Nat Biotechnol. 2014;32:1121–33.CrossRefGoogle Scholar
  38. 38.
    Pagliuca FW, Millman JR, Gürtler M, Segel M, van Dervort A, Ryu JH, et al. Generation of functional human pancreatic β cells in vitro. Cell. 2014;159:428–39.CrossRefGoogle Scholar
  39. 39.
    Millman JR, et al. Generation of stem cell-derived β-cells from patients with type 1 diabetes. Nat Commun. 2016;7:11463.CrossRefGoogle Scholar
  40. 40.
    Petersen MBK, Azad A, Ingvorsen C, Hess K, Hansson M, Grapin-Botton A, 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. 2017;9:1246–61.CrossRefGoogle Scholar
  41. 41.
    Okita K, Ichisaka T, Yamanaka S. Generation of germline-competent induced pluripotent stem cells. Nature. 2007;448:313–7.CrossRefGoogle Scholar
  42. 42.
    Ferber S, Halkin A, Cohen H, Ber I, Einav Y, Goldberg I, et al. Pancreatic and duodenal homeobox gene 1 induces expression of insulin genes in liver and ameliorates streptozotocin-induced hyperglycemia. Nat Med. 2000;6:568–72.CrossRefGoogle Scholar
  43. 43.
    Kojima H, et al. NeuroD-betacellulin gene therapy induces islet neogenesis in the liver and reverses diabetes in mice. Nat Med. 2003;9:596–603.CrossRefGoogle Scholar
  44. 44.
    Zhou Q, Brown J, Kanarek A, Rajagopal J, Melton DA. In vivo reprogramming of adult pancreatic exocrine cells to β-cells. Nature. 2008;455:627–32.CrossRefGoogle Scholar
  45. 45.
    Li W, Cavelti-Weder C, Zhang Y, Clement K, Donovan S, Gonzalez G, et al. Long-term persistence and development of induced pancreatic beta cells generated by lineage conversion of acinar cells. Nat Biotechnol. 2014;32:1223–30.CrossRefGoogle Scholar
  46. 46.
    Baeyens L, et al. Transient cytokine treatment induces acinar cell reprogramming and regenerates functional beta cell mass in diabetic mice. Nat Biotechnol. 2014;32:76–83.CrossRefGoogle Scholar
  47. 47.
    Akinci E, Banga A, Greder LV, Dutton JR, Slack JMW. Reprogramming of pancreatic exocrine cells towards a beta (β) cell character using Pdx1, Ngn3 and MafA. Biochem J. 2012;442:539–50.CrossRefGoogle Scholar
  48. 48.
    Ariyachet C, Tovaglieri A, Xiang G, Lu J, Shah MS, Richmond CA, et al. Reprogrammed stomach tissue as a renewable source of functional β cells for blood glucose regulation. Cell Stem Cell. 2016;18:410–21.CrossRefGoogle Scholar
  49. 49.
    Bar-Nur O, Russ HA, Efrat S, Benvenisty N. Epigenetic memory and preferential lineage-specific differentiation in induced pluripotent stem cells derived from human pancreatic islet beta cells. Cell Stem Cell. 2011;9:17–23.CrossRefGoogle Scholar
  50. 50.
    Bramswig NC, Everett LJ, Schug J, Dorrell C, Liu C, Luo Y, et al. Epigenomic plasticity enables human pancreatic alpha to beta cell reprogramming. J Clin Invest. 2013;123:1275–84.Google Scholar
  51. 51.
    Xiao X, Guo P, Shiota C, Zhang T, Coudriet GM, Fischbach S, et al. Endogenous reprogramming of alpha cells into beta, induced by viral gene therapy, reverses autoimmune diabetes. Cell Stem Cell. 2018;22:78–90.CrossRefGoogle Scholar
  52. 52.
    Lemper M, Leuckx G, Heremans Y, German MS, Heimberg H, Bouwens L, et al. Reprogramming of human pancreatic exocrine cells to β-like cells. Cell Death Differ. 2015;22:1117–30.CrossRefGoogle Scholar
  53. 53.
    Vegas AJ, et al. Long-term glycemic control using polymer-encapsulated human stem cell-derived beta cells in immune-competent mice. Nat Med. 2016;22:306–11.CrossRefGoogle Scholar

Copyright information

© The Regenerative Engineering Society 2018

Authors and Affiliations

  • Lauren N. Randolph
    • 1
    • 2
  • Agamoni Bhattacharyya
    • 1
    • 2
  • Xiaojun Lance Lian
    • 1
    • 2
    • 3
    Email author
  1. 1.Department of Biomedical EngineeringPennsylvania State UniversityUniversity ParkUSA
  2. 2.The Huck Institutes of the Life SciencesPennsylvania State UniversityUniversity ParkUSA
  3. 3.Department of BiologyPennsylvania State UniversityUniversity ParkUSA

Personalised recommendations