Advertisement

Diabetologia

, Volume 57, Issue 7, pp 1420–1427 | Cite as

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

  • Ying Cai
  • Yixing Yuchi
  • Sofie De Groef
  • Violette Coppens
  • Gunter Leuckx
  • Luc Baeyens
  • Mark Van de Casteele
  • Harry HeimbergEmail author
Article

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.

Keywords

Alpha cell Beta cell Diabetes Glucagon IL-6 Islet Neogenesis Partial duct ligation Proliferation Reprogramming 

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

Notes

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.

Supplementary material

125_2014_3242_MOESM1_ESM.pdf (406 kb)
ESM Fig. 1 (PDF 405 kb)
125_2014_3242_MOESM2_ESM.pdf (393 kb)
ESM Fig. 2 (PDF 392 kb)
125_2014_3242_MOESM3_ESM.pdf (232 kb)
ESM Fig. 3 (PDF 232 kb)
125_2014_3242_MOESM4_ESM.pdf (625 kb)
ESM Fig. 4 (PDF 625 kb)
125_2014_3242_MOESM5_ESM.pdf (241 kb)
ESM Fig. 5 (PDF 241 kb)
125_2014_3242_MOESM6_ESM.pdf (47 kb)
ESM Table 1 (PDF 47 kb)

References

  1. 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 429:41–46PubMedCrossRefGoogle Scholar
  2. 2.
    Nir T, Melton DA, Dor Y (2007) Recovery from diabetes in mice by β cell regeneration. J Clin Invest 117:2553–2561PubMedCentralPubMedCrossRefGoogle Scholar
  3. 3.
    Teta M, Rankin MM, Long SY et al (2007) Growth and regeneration of adult β cells does not involve specialized progenitors. Dev Cell 12:817–826PubMedCrossRefGoogle Scholar
  4. 4.
    Zhou Q, Brown J, Kanarek A et al (2008) In vivo reprogramming of adult pancreatic exocrine cells to β-cells. Nature 455:627–632PubMedCrossRefGoogle Scholar
  5. 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 132:197–207PubMedCrossRefGoogle Scholar
  6. 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 140:751–764PubMedCentralPubMedCrossRefGoogle Scholar
  7. 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 138:449–462PubMedCentralPubMedCrossRefGoogle Scholar
  8. 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 26:86–100PubMedCrossRefGoogle Scholar
  9. 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 464:1149–1154PubMedCentralPubMedCrossRefGoogle Scholar
  10. 10.
    Habener JF, Stanojevic V (2012) α-Cell role in β-cell generation and regeneration. Islets 4:188–198PubMedCentralPubMedCrossRefGoogle Scholar
  11. 11.
    Habener JF, Stanojevic V (2013) Alpha cells come of age. Trends Endocrinol Metab 24:153–163PubMedCrossRefGoogle Scholar
  12. 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:e523PubMedCentralPubMedCrossRefGoogle Scholar
  13. 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 43:34–41PubMedCrossRefGoogle Scholar
  14. 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 38:1405–1411PubMedCrossRefGoogle Scholar
  15. 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 62:1634–1645PubMedCentralPubMedCrossRefGoogle Scholar
  16. 16.
    Xiao X, Chen Z, Shiota C et al (2013) No evidence for β cell neogenesis in murine adult pancreas. J Clin Invest 123:2207–2217PubMedCentralPubMedCrossRefGoogle Scholar
  17. 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 19:637–644PubMedCrossRefGoogle Scholar
  18. 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 105:13163–13168PubMedCentralPubMedCrossRefGoogle Scholar
  19. 19.
    Grouwels G, Cai Y, Hoebeke I et al (2010) Ectopic expression of E2F1 stimulates beta-cell proliferation and function. Diabetes 59:1435–1444PubMedCentralPubMedCrossRefGoogle Scholar
  20. 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 145:4185–4191PubMedGoogle Scholar
  21. 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 1:4PubMedCentralPubMedCrossRefGoogle Scholar
  22. 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 47:646–652PubMedCrossRefGoogle Scholar
  23. 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–G836PubMedGoogle Scholar
  24. 24.
    Talchai C, Xuan S, Lin HV et al (2012) Pancreatic β cell dedifferentiation as a mechanism of diabetic β cell failure. Cell 150:1223–1234PubMedCentralPubMedCrossRefGoogle Scholar
  25. 25.
    Katsuta H, Akashi T, Katsuta R et al (2009) Single pancreatic beta cells co-express multiple islet hormone genes in mice. Diabetologia 53:128–138PubMedCentralPubMedCrossRefGoogle Scholar
  26. 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 117:961–970PubMedCentralPubMedCrossRefGoogle Scholar
  27. 27.
    Spijker HS, Ravelli RBG, Mommaas-Kienhuis AM et al (2013) Conversion of mature human β-cells into glucagon-producing α-cells. Diabetes 62:2471–2480PubMedCrossRefGoogle Scholar
  28. 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 62:1217–1226PubMedCrossRefGoogle Scholar
  29. 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 17:1481–1489PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Ying Cai
    • 1
  • Yixing Yuchi
    • 1
  • Sofie De Groef
    • 1
  • Violette Coppens
    • 1
  • Gunter Leuckx
    • 1
  • Luc Baeyens
    • 1
  • Mark Van de Casteele
    • 1
  • Harry Heimberg
    • 1
    Email author
  1. 1.Diabetes Research CenterVrije Universiteit BrusselBrusselsBelgium

Personalised recommendations