Skip to main content

Advertisement

SpringerLink
Log in

IL-6-dependent proliferation of alpha cells in mice with partial pancreatic-duct ligation

  • Article
  • Published:
Diabetologia Aims and scope Submit manuscript

Abstract

Aims/hypothesis

IL-6 was recently shown to control alpha cell expansion. As beta cells expand following partial pancreatic-duct ligation (PDL) in adult mice, we investigated whether PDL also causes alpha cells to expand and whether IL-6 signalling is involved. As alpha cells can reprogramme to beta cells in a number of beta cell (re)generation models, we examined whether this phenomenon also exists in PDL pancreas.

Methods

Total alpha cell volume, alpha cell size and total glucagon content were evaluated in equivalent portions of PDL- and sham-operated mouse pancreases. Proliferation of glucagon+ cells was assessed by expression of the proliferation marker Ki67. Inter-conversions between alpha and beta cells were monitored in transgenic mice with conditional cell-type-specific labelling. The role of IL-6 in regulating alpha cell proliferation was evaluated by in situ delivery of an IL-6-inactivating antibody.

Results

In response to PDL surgery, alpha cell volume in the ligated tissue was increased threefold, glucagon content fivefold and alpha cell size by 10%. Activation of alpha cell proliferation in PDL pancreas required IL-6 signalling. A minor fraction of alpha cells derived from beta cells, whereas no evidence for alpha to beta cell conversion was obtained.

Conclusions/interpretation

In PDL-injured adult mouse pancreas, new alpha cells are generated mainly by IL-6-dependent self-duplication and seldom by reprogramming of beta cells.

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

Similar content being viewed by others

Abbreviations

Dox:

Doxycycline

GLP-1:

Glucagon-like peptide-1

GFP:

Green fluorescent protein

IL-6R:

IL-6-receptor

MAFB:

V-maf musculoaponeurotic fibrosarcoma oncogene family, protein B (avian)

PDL:

Partial pancreatic-duct ligation

Pro-hormone convertases 1/3 and 2:

PC1/3 and PC2

rtTA:

Reverse tetracycline transactivator

STAT3:

Signal transducer and activator of transcription 3

Tam:

Tamoxifen

YFP:

Yellow fluorescent protein

References

  1. Dor Y, Brown J, Martinez OI, Melton DA (2004) Adult pancreatic β-cells are formed by self-duplication rather than stem-cell differentiation. Nature 429:41–46

    Article  CAS  PubMed  Google Scholar 

  2. Nir T, Melton DA, Dor Y (2007) Recovery from diabetes in mice by β cell regeneration. J Clin Invest 117:2553–2561

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  3. Teta M, Rankin MM, Long SY et al (2007) Growth and regeneration of adult β cells does not involve specialized progenitors. Dev Cell 12:817–826

    Article  CAS  PubMed  Google Scholar 

  4. Zhou Q, Brown J, Kanarek A et al (2008) In vivo reprogramming of adult pancreatic exocrine cells to β-cells. Nature 455:627–632

    Article  CAS  PubMed  Google Scholar 

  5. Xu X, D’Hoker J, Stangé G et al (2008) Beta cells can be generated from endogenous progenitors in injured adult mouse pancreas. Cell 132:197–207

    Article  CAS  PubMed  Google Scholar 

  6. Pan FC, Bankaitis ED, Boyer D et al (2013) Spatiotemporal patterns of multipotentiality in Ptf1a-expressing cells during pancreas organogenesis and injury-induced facultative restoration. Development 140:751–764

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  7. Collombat P, Xu X, Ravassard P et al (2009) The ectopic expression of Pax4 in the mouse pancreas converts progenitor cells into alpha- and subsequently beta cells. Cell 138:449–462

    Article  CAS  PubMed Central  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  9. Thorel F, Népote V, Avril I et al (2010) Conversion of adult pancreatic alpha-cells to beta-cells after extreme beta-cell loss. Nature 464:1149–1154

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  10. Habener JF, Stanojevic V (2012) α-Cell role in β-cell generation and regeneration. Islets 4:188–198

    Article  PubMed Central  PubMed  Google Scholar 

  11. Habener JF, Stanojevic V (2013) Alpha cells come of age. Trends Endocrinol Metab 24:153–163

    Article  CAS  PubMed  Google Scholar 

  12. Van de Casteele M, Leuckx G, Baeyens L et al (2013) Neurogenin 3(+) cells contribute to β-cell neogenesis and proliferation in injured adult mouse pancreas. Cell Death Dis 4:e523

    Article  PubMed Central  PubMed  Google Scholar 

  13. Furuyama K, Kawaguchi Y, Akiyama H et al (2010) Continuous cell supply from a Sox9-expressing progenitor zone in adult liver, exocrine pancreas and intestine. Nat Genet 43:34–41

    Article  PubMed  Google Scholar 

  14. Wang RN, Klöppel G, Bouwens L (1995) Duct- to islet-cell differentiation and islet growth in the pancreas of duct-ligated adult rats. Diabetologia 38:1405–1411

    Article  CAS  PubMed  Google Scholar 

  15. Rankin MM, Wilbur CJ, Rak K et al (2013) Beta cells are not generated in pancreatic duct ligation induced injury in adult mice. Diabetes 62:1634–1645

    Article  CAS  PubMed Central  PubMed  Google Scholar 

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

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  17. Yasuda H, Kataoka K, Ichimura H et al (1999) Cytokine expression and induction of acinar cell apoptosis after pancreatic duct ligation in mice. J Interferon Cytokine Res 19:637–644

    Article  CAS  PubMed  Google Scholar 

  18. Ellingsgaard H, Ehses JA, Hammar EB et al (2008) Interleukin-6 regulates pancreatic alpha-cell mass expansion. Proc Natl Acad Sci U S A 105:13163–13168

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  19. Grouwels G, Cai Y, Hoebeke I et al (2010) Ectopic expression of E2F1 stimulates beta-cell proliferation and function. Diabetes 59:1435–1444

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  20. Starnes HF, Pearce MK, Tewari A et al (1990) Anti-IL-6 monoclonal antibodies protect against lethal Escherichia coli infection and lethal tumor necrosis factor-alpha challenge in mice. J Immunol 145:4185–4191

    CAS  PubMed  Google Scholar 

  21. Srinivas S, Watanabe T, Lin CS et al (2001) Cre reporter strains produced by targeted insertion of EYFP and ECFP into the ROSA26 locus. BMC Dev Biol 1:4

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  22. Flamez D, Van Breusegem A, Scrocchi LA et al (1998) Mouse pancreatic beta-cells exhibit preserved glucose competence after disruption of the glucagon-like peptide-1 receptor gene. Diabetes 47:646–652

    Article  CAS  PubMed  Google Scholar 

  23. Scoggins CR, Meszoely IM, Wada M et al (2000) p53-dependent acinar cell apoptosis triggers epithelial proliferation in duct-ligated murine pancreas. Am J Physiol Gastrointest Liver Physiol 279:G827–G836

    CAS  PubMed  Google Scholar 

  24. Talchai C, Xuan S, Lin HV et al (2012) Pancreatic β cell dedifferentiation as a mechanism of diabetic β cell failure. Cell 150:1223–1234

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  25. Katsuta H, Akashi T, Katsuta R et al (2009) Single pancreatic beta cells co-express multiple islet hormone genes in mice. Diabetologia 53:128–138

    Article  PubMed Central  PubMed  Google Scholar 

  26. Collombat P, Hecksher-Sorensen J, Krull J et al (2007) Embryonic endocrine pancreas and mature β cells acquire α and PP cell phenotypes upon Arx misexpression. J Clin Invest 117:961–970

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  27. Spijker HS, Ravelli RBG, Mommaas-Kienhuis AM et al (2013) Conversion of mature human β-cells into glucagon-producing α-cells. Diabetes 62:2471–2480

    Article  CAS  PubMed  Google Scholar 

  28. Xiao X, Wiersch J, El-Gohary Y et al (2012) TGFβ receptor signaling is essential for inflammation-induced but not β-cell workload-induced β-cell proliferation. Diabetes 62:1217–1226

    Article  PubMed  Google Scholar 

  29. Ellingsgaard H, Hauselmann I, Schuler B et al (2011) Interleukin-6 enhances insulin secretion by increasing glucagon-like peptide-1 secretion from L cells and alpha cells. Nat Med 17:1481–1489

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank A. Demarré, V. Laurysens, J. de Jonge, E. Quartier, R. de Proft and G. Schoonjans (Diabetes Research Center, Vrije Universiteit Brussel, Brussels, Belgium) for technical assistance, and P. Herrera (University of Geneva, Geneva, Suisse) for sharing the Gcg rtTA/TetO Cre mice.

Funding

Financial support was from the VUB Research Council (HH, MVdC), the Institute for the Promotion of Innovation by Science and Technology in Flanders (IWT) (HH, VC), the Chinese Scholarship Council (YY), the Innovative Medicines Initiative Joint Undertaking under grant agreement number 155005 (IMIDIA) composed of financial contributions from the European Union’s Seventh Framework Programme (FP7/2007-2013) and EFPIA companies in kind contribution (HH), Stichting Diabetes Onderzoek Nederland (HH), the Fund for Scientific Research Flanders (FWO) (HH, SDG) and the Interuniversity Attraction Pole networks (HH).

Duality of interest

The authors declare that there is no duality of interest associated with this manuscript.

Contribution statement

All authors were involved in the acquisition, analysis or interpretation of data and drafting of the manuscript. YC, YY, MVdC and HH were involved in the study concept and design and critical revision of the manuscript. All authors approved the final version of the manuscript.

HH is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Author information

Authors and Affiliations

  1. Diabetes Research Center, Vrije Universiteit Brussel, Laarbeeklaan 103, B1090, Brussels, Belgium

    Ying Cai, Yixing Yuchi, Sofie De Groef, Violette Coppens, Gunter Leuckx, Luc Baeyens, Mark Van de Casteele & Harry Heimberg

Authors
  1. Ying Cai
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yixing Yuchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sofie De Groef
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Violette Coppens
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Gunter Leuckx
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Luc Baeyens
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Mark Van de Casteele
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Harry Heimberg
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Harry Heimberg.

Additional information

Ying Cai and Yixing Yuchi are joint first authors of this article.

Mark Van de Casteele and Harry Heimberg are joint senior authors of this article.

Electronic supplementary material

Below is the link to the electronic supplementary material.

ESM Fig. 1

(PDF 405 kb)

ESM Fig. 2

(PDF 392 kb)

ESM Fig. 3

(PDF 232 kb)

ESM Fig. 4

(PDF 625 kb)

ESM Fig. 5

(PDF 241 kb)

ESM Table 1

(PDF 47 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Cai, Y., Yuchi, Y., De Groef, S. et al. IL-6-dependent proliferation of alpha cells in mice with partial pancreatic-duct ligation. Diabetologia 57, 1420–1427 (2014). https://doi.org/10.1007/s00125-014-3242-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00125-014-3242-8

Keywords

Search

Navigation