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Erschienen in:

01.07.2014 | Article

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

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

Erschienen in: Diabetologia | Ausgabe 7/2014

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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.

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

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

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

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

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

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 140:751–764PubMedCentralPubMedCrossRef

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 138:449–462PubMedCentralPubMedCrossRef

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 26:86–100PubMedCrossRef

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

10.

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

11.

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

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:e523PubMedCentralPubMedCrossRef

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 43:34–41PubMedCrossRef

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 38:1405–1411PubMedCrossRef

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 62:1634–1645PubMedCentralPubMedCrossRef

16.

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

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 19:637–644PubMedCrossRef

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 105:13163–13168PubMedCentralPubMedCrossRef

19.

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

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 145:4185–4191PubMed

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 1:4PubMedCentralPubMedCrossRef

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 47:646–652PubMedCrossRef

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–G836PubMed

24.

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

25.

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

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 117:961–970PubMedCentralPubMedCrossRef

27.

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

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 62:1217–1226PubMedCrossRef

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 17:1481–1489PubMedCrossRef

Titel: IL-6-dependent proliferation of alpha cells in mice with partial pancreatic-duct ligation
verfasst von: Ying Cai
Yixing Yuchi
Sofie De Groef
Violette Coppens
Gunter Leuckx
Luc Baeyens
Mark Van de Casteele
Harry Heimberg
Publikationsdatum: 01.07.2014
Verlag: Springer Berlin Heidelberg
Erschienen in: Diabetologia / Ausgabe 7/2014
Print ISSN: 0012-186X
Elektronische ISSN: 1432-0428
DOI: https://doi.org/10.1007/s00125-014-3242-8

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Abstract

Aims/hypothesis

Methods

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