Skip to main content
SpringerLink
Log in

Uncovering the mechanisms of beta-cell neogenesis and maturation toward development of a regenerative therapy for diabetes

  • Review Article
  • Published:
Diabetology International Aims and scope Submit manuscript

Abstract

Knowledge of the pathways involved in islet cell differentiation has been exploited to develop new methods for generating beta cells from non-beta cells, such as embryonic stem cells and pancreatic acinar cells, which should lead to the development of future cell therapies for the cure of diabetes. However, these methods do not enable insulin-producing cells to complete their final maturation to fully functional beta cells that are capable of producing high levels of insulin and of responding to normal physiological signals. This obstacle arises from our lack of a complete understanding of how the pancreas is formed and how beta cells differentiate from their precursors during development. Here I review the recent progress in our understanding of the molecular mechanisms controlling beta-cell neogenesis and maturation.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Zhou Q, Brown J, Kanarek A, Rajagopal J, Melton DA. In vivo reprogramming of adult pancreatic exocrine cells to beta-cells. Nature. 2008;455:627–32.

    Article  CAS  PubMed  Google Scholar 

  2. Banga A, Akinci E, Greder LV, Dutton JR, Slack JM. In vivo reprogramming of Sox9+ cells in the liver to insulin-secreting ducts. Proc Natl Acad Sci USA. 2012;109:15336–41.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  3. Miyashita K, Miyatsuka T, Matsuoka TA, Sasaki S, Takebe S, Yasuda T, Watada H, Kaneto H, Shimomura I. Sequential introduction and dosage balance of defined transcription factors affect reprogramming efficiency from pancreatic duct cells into insulin-producing cells. Biochem Biophys Res Commun. 2014;444:514–9.

    Article  CAS  PubMed  Google Scholar 

  4. Chen YJ, Finkbeiner SR, Weinblatt D, Emmett MJ, Tameire F, Yousefi M, Yang C, Maehr R, Zhou Q, Shemer R, Dor Y, Li C, Spence JR, Stanger BZ. De novo formation of insulin-producing “neo-beta cell islets” from intestinal crypts. Cell Rep. 2014;6:1046–58.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  5. Li W, Cavelti-Weder C, Zhang Y, Clement K, Donovan S, Gonzalez G, Zhu J, Stemann M, Xu K, Hashimoto T, Yamada T, Nakanishi M, Zhang Y, Zeng S, Gifford D, Meissner A, Weir G, Zhou Q. Long-term persistence and development of induced pancreatic beta cells generated by lineage conversion of acinar cells. Nat Biotechnol. 2014;32:1223–30.

    Article  CAS  PubMed  Google Scholar 

  6. Miyatsuka T, Matsuoka TA, Kaneto H. Transcription factors as therapeutic targets for diabetes. Expert Opin Ther Targets. 2008;12:1431–42.

    Article  CAS  PubMed  Google Scholar 

  7. Oliver-Krasinski JM, Stoffers DA. On the origin of the beta cell. Genes Dev. 2008;22:1998–2021.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  8. Puri S, Hebrok M. Cellular plasticity within the pancreas—lessons learned from development. Dev Cell. 2010;18:342–56.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  9. Jonsson J, Carlsson L, Edlund T, Edlund H. Insulin-promoter-factor 1 is required for pancreas development in mice. Nature. 1994;371:606–9.

    Article  CAS  PubMed  Google Scholar 

  10. Ahlgren U, Jonsson J, Edlund H. The morphogenesis of the pancreatic mesenchyme is uncoupled from that of the pancreatic epithelium in IPF1/PDX1-deficient mice. Development. 1996;122:1409–16.

    CAS  PubMed  Google Scholar 

  11. Offield MF, Jetton TL, Labosky PA, Ray M, Stein RW, Magnuson MA, Hogan BL, Wright CV. PDX-1 is required for pancreatic outgrowth and differentiation of the rostral duodenum. Development. 1996;122:983–95.

    CAS  PubMed  Google Scholar 

  12. Ahlgren U, Jonsson J, Jonsson L, Simu K, Edlund H. Beta-cell-specific inactivation of the mouse Ipf1/Pdx1 gene results in loss of the beta-cell phenotype and maturity onset diabetes. Genes Dev. 1998;12:1763–8.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  13. Dutta S, Bonner-Weir S, Montminy M, Wright C. Regulatory factor linked to late-onset diabetes? Nature. 1998;392:560.

    Article  CAS  PubMed  Google Scholar 

  14. Johnson JD, Ahmed NT, Luciani DS, Han Z, Tran H, Fujita J, Misler S, Edlund H, Polonsky KS. Increased islet apoptosis in Pdx1±mice. J Clin Investig. 2003;111:1147–60.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  15. Gu G, Dubauskaite J, Melton DA. Direct evidence for the pancreatic lineage: NGN3+ cells are islet progenitors and are distinct from duct progenitors. Development. 2002;129:2447–57.

    CAS  PubMed  Google Scholar 

  16. Stoffers DA, Zinkin NT, Stanojevic V, Clarke WL, Habener JF. Pancreatic agenesis attributable to a single nucleotide deletion in the human IPF1 gene coding sequence. Nat Genet. 1997;15:106–10.

    Article  CAS  PubMed  Google Scholar 

  17. Ohlsson H, Karlsson K, Edlund T. IPF1, a homeodomain-containing transactivator of the insulin gene. EMBO J. 1993;12:4251–9.

    PubMed Central  CAS  PubMed  Google Scholar 

  18. Waeber G, Thompson N, Nicod P, Bonny C. Transcriptional activation of the GLUT2 gene by the IPF-1/STF-1/IDX-1 homeobox factor. Mol Endocrinol. 1996;10:1327–34.

    CAS  PubMed  Google Scholar 

  19. Watada H, Kajimoto Y, Umayahara Y, Matsuoka T, Kaneto H, Fujitani Y, Kamada T, Kawamori R, Yamasaki Y. The human glucokinase gene beta-cell-type promoter: an essential role of insulin promoter factor 1/PDX-1 in its activation in HIT-T15 cells. Diabetes. 1996;45:1478–88.

    Article  CAS  PubMed  Google Scholar 

  20. Kulkarni RN, Jhala US, Winnay JN, Krajewski S, Montminy M, Kahn CR. PDX-1 haploinsufficiency limits the compensatory islet hyperplasia that occurs in response to insulin resistance. J Clin Investig. 2004;114:828–36.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  21. Stoffers DA, Ferrer J, Clarke WL, Habener JF. Early-onset type-II diabetes mellitus (MODY4) linked to IPF1. Nat Genet. 1997;17:138–9.

    Article  CAS  PubMed  Google Scholar 

  22. Watada H, Kajimoto Y, Miyagawa J, Hanafusa T, Hamaguchi K, Matsuoka T, Yamamoto K, Matsuzawa Y, Kawamori R, Yamasaki Y. PDX-1 induces insulin and glucokinase gene expressions in alphaTC1 clone 6 cells in the presence of betacellulin. Diabetes. 1996;45:1826–31.

    Article  CAS  PubMed  Google Scholar 

  23. Serup P, Jensen J, Andersen FG, Jorgensen MC, Blume N, Holst JJ, Madsen OD. Induction of insulin and islet amyloid polypeptide production in pancreatic islet glucagonoma cells by insulin promoter factor 1. Proc Natl Acad Sci USA. 1996;93:9015–20.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  24. Kojima H, Nakamura T, Fujita Y, Kishi A, Fujimiya M, Yamada S, Kudo M, Nishio Y, Maegawa H, Haneda M, Yasuda H, Kojima I, Seno M, Wong NC, Kikkawa R, Kashiwagi A. Combined expression of pancreatic duodenal homeobox 1 and islet factor 1 induces immature enterocytes to produce insulin. Diabetes. 2002;51:1398–408.

    Article  CAS  PubMed  Google Scholar 

  25. Yoshida S, Kajimoto Y, Yasuda T, Watada H, Fujitani Y, Kosaka H, Gotow T, Miyatsuka T, Umayahara Y, Yamasaki Y, Hori M. PDX-1 induces differentiation of intestinal epithelioid IEC-6 into insulin-producing cells. Diabetes. 2002;51:2505–13.

    Article  CAS  PubMed  Google Scholar 

  26. Ferber S, Halkin A, Cohen H, Ber I, Einav Y, Goldberg I, Barshack I, Seijffers R, Kopolovic J, Kaiser N, Karasik A. Pancreatic and duodenal homeobox gene 1 induces expression of insulin genes in liver and ameliorates streptozotocin-induced hyperglycemia. Nat Med. 2000;6:568–72.

    Article  CAS  PubMed  Google Scholar 

  27. Taniguchi H, Yamato E, Tashiro F, Ikegami H, Ogihara T, Miyazaki J. Beta-cell neogenesis induced by adenovirus-mediated gene delivery of transcription factor pdx-1 into mouse pancreas. Gene Ther. 2003;10:15–23.

    Article  CAS  PubMed  Google Scholar 

  28. Miyatsuka T, Kaneto H, Kajimoto Y, Hirota S, Arakawa Y, Fujitani Y, Umayahara Y, Watada H, Yamasaki Y, Magnuson MA, Miyazaki J, Hori M. Ectopically expressed PDX-1 in liver initiates endocrine and exocrine pancreas differentiation but causes dysmorphogenesis. Biochem Biophys Res Commun. 2003;310:1017–25.

    Article  CAS  PubMed  Google Scholar 

  29. Kaneto H, Nakatani Y, Miyatsuka T, Matsuoka TA, Matsuhisa M, Hori M, Yamasaki Y. PDX-1/VP16 fusion protein, together with NeuroD or Ngn3, markedly induces insulin gene transcription and ameliorates glucose tolerance. Diabetes. 2005;54:1009–22.

    Article  CAS  PubMed  Google Scholar 

  30. Kaneto H, Matsuoka TA, Nakatani Y, Miyatsuka T, Matsuhisa M, Hori M, Yamasaki Y. A crucial role of MafA as a novel therapeutic target for diabetes. J Biol Chem. 2005;280:15047–52.

    Article  CAS  PubMed  Google Scholar 

  31. Kawaguchi Y, Cooper B, Gannon M, Ray M, MacDonald RJ, Wright CV. The role of the transcriptional regulator Ptf1a in converting intestinal to pancreatic progenitors. Nat Genet. 2002;32:128–34.

    Article  CAS  PubMed  Google Scholar 

  32. Miyatsuka T, Kaneto H, Shiraiwa T, Matsuoka TA, Yamamoto K, Kato K, Nakamura Y, Akira S, Takeda K, Kajimoto Y, Yamasaki Y, Sandgren EP, Kawaguchi Y, Wright CV, Fujitani Y. Persistent expression of PDX-1 in the pancreas causes acinar-to-ductal metaplasia through Stat3 activation. Genes Dev. 2006;20:1435–40.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  33. Stoffers DA, Heller RS, Miller CP, Habener JF. Developmental expression of the homeodomain protein IDX-1 in mice transgenic for an IDX-1 promoter/lacZ transcriptional reporter. Endocrinology. 1999;140:5374–81.

    CAS  PubMed  Google Scholar 

  34. Greten FR, Weber CK, Greten TF, Schneider G, Wagner M, Adler G, Schmid RM. Stat3 and NF-kappaB activation prevents apoptosis in pancreatic carcinogenesis. Gastroenterology. 2002;123:2052–63.

    Article  CAS  PubMed  Google Scholar 

  35. Apelqvist A, Li H, Sommer L, Beatus P, Anderson DJ, Honjo T, Hrabe de Angelis M, Lendahl U, Edlund H. Notch signalling controls pancreatic cell differentiation. Nature. 1999;400:877–81.

    Article  CAS  PubMed  Google Scholar 

  36. 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. 2000;97:1607–11.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  37. Gasa R, Mrejen C, Leachman N, Otten M, Barnes M, Wang J, Chakrabarti S, Mirmira R, German M. Proendocrine genes coordinate the pancreatic islet differentiation program in vitro. Proc Natl Acad Sci USA. 2004;101:13245–50.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  38. Xu X, D’Hoker J, Stange G, Bonne S, De Leu N, Xiao X, Van de Casteele M, Mellitzer G, Ling Z, Pipeleers D, Bouwens L, Scharfmann R, Gradwohl G, Heimberg H. Beta cells can be generated from endogenous progenitors in injured adult mouse pancreas. Cell. 2008;132:197–207.

    Article  CAS  PubMed  Google Scholar 

  39. Miyatsuka T, Li Z, German MS. Chronology of islet differentiation revealed by temporal cell labeling. Diabetes. 2009;58:1863–8.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  40. Terskikh A, Fradkov A, Ermakova G, Zaraisky A, Tan P, Kajava AV, Zhao X, Lukyanov S, Matz M, Kim S, Weissman I, Siebert P. “Fluorescent timer”: protein that changes color with time. Science. 2000;290:1585–8.

    Article  CAS  PubMed  Google Scholar 

  41. Miyatsuka T, Kosaka Y, Kim H, German MS. Neurogenin3 inhibits proliferation in endocrine progenitors by inducing Cdkn1a. Proc Natl Acad Sci USA. 2011;108:185–90.

    Article  PubMed Central  PubMed  Google Scholar 

  42. Miyatsuka T, Matsuoka TA, Sasaki S, Kubo F, Shimomura I, Watada H, German MS, Hara M. Chronological analysis with fluorescent timer reveals unique features of newly generated beta-cells. Diabetes. 2014;63:3388–93.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  43. Dor Y, Brown J, Martinez OI, Melton DA. Adult pancreatic beta-cells are formed by self-duplication rather than stem-cell differentiation. Nature. 2004;429:41–6.

    Article  CAS  PubMed  Google Scholar 

  44. Teta M, Rankin MM, Long SY, Stein GM, Kushner JA. Growth and regeneration of adult beta cells does not involve specialized progenitors. Dev Cell. 2007;12:817–26.

    Article  CAS  PubMed  Google Scholar 

  45. Xiao X, Chen Z, Shiota C, Prasadan K, Guo P, El-Gohary Y, Paredes J, Welsh C, Wiersch J, Gittes GK. No evidence for beta cell neogenesis in murine adult pancreas. J Clin Investig. 2013;123:2207–17.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  46. Baeyens L, Lemper M, Leuckx G, De Groef S, Bonfanti P, Stange G, Shemer R, Nord C, Scheel DW, Pan FC, Ahlgren U, Gu G, Stoffers DA, Dor Y, Ferrer J, Gradwohl G, Wright CV, Van de Casteele M, German MS, Bouwens L, Heimberg H. Transient cytokine treatment induces acinar cell reprogramming and regenerates functional beta cell mass in diabetic mice. Nat Biotechnol. 2014;32:76–83.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  47. Sasaki S, Miyatsuka T, Matsuoka T, Takahara M, Yamamoto Y, Yasuda T, Kaneto H, Fujitani Y, German MS, Akiyama H, Watada H, Shimomura I. Activation of GLP-1 and gastrin signaling induces in vivo reprogramming of pancreatic exocrine cells into beta cells. Diabetologia. 2015 [Epub ahead of print].

  48. Furuyama K, Kawaguchi Y, Akiyama H, Horiguchi M, Kodama S, Kuhara T, Hosokawa S, Elbahrawy A, Soeda T, Koizumi M, Masui T, Kawaguchi M, Takaori KR, Nishi E, Kakinoki R, Deng JM, Behringer RR, Nakamura T, Uemoto S. Continuous cell supply from a Sox9-expressing progenitor zone in adult liver, exocrine pancreas and intestine. Nat Genet. 2011;43:34–41.

    Article  CAS  PubMed  Google Scholar 

  49. Gier B, Matveyenko AV, Kirakossian D, Dawson D, Dry SM, Butler PC. Chronic GLP-1 receptor activation by exendin-4 induces expansion of pancreatic duct glands in rats and accelerates formation of dysplastic lesions and chronic pancreatitis in the Kras(G12D) mouse model. Diabetes. 2012;61:1250–62.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  50. Butler PC, Elashoff M, Elashoff R, Gale EA. A critical analysis of the clinical use of incretin-based therapies: are the GLP-1 therapies safe? Diabetes Care. 2013;36:2118–25.

    Article  PubMed Central  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-Ku, Tokyo, 113-8421, Japan

    Takeshi Miyatsuka

  2. Center for Molecular Diabetology, Juntendo University Graduate School of Medicine, Tokyo, Japan

    Takeshi Miyatsuka

  3. Department of Metabolic Medicine, Osaka University Graduate School of Medicine, Osaka, Japan

    Takeshi Miyatsuka

Authors
  1. Takeshi Miyatsuka
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Takeshi Miyatsuka.

Ethics declarations

Conflict of interest

The author declares that there is no conflict of interest associated with this manuscript.

Ethical standard

All institutional and national guidelines for the care and use of laboratory animals were followed.

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Miyatsuka, T. Uncovering the mechanisms of beta-cell neogenesis and maturation toward development of a regenerative therapy for diabetes. Diabetol Int 6, 261–267 (2015). https://doi.org/10.1007/s13340-015-0233-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13340-015-0233-z

Keywords

Search

Navigation