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Identification of markers for quiescent pancreatic stellate cells in the normal human pancreas

Abstract

Pancreatic stellate cells (PSCs) play a central role as source of fibrogenic cells in pancreatic cancer and chronic pancreatitis. In contrast to quiescent hepatic stellate cells (qHSCs), a specific marker for quiescent PSCs (qPSCs) that can be used in formalin-fixed and paraffin embedded (FFPE) normal human pancreatic tissue has not been identified. The aim of this study was to identify a marker enabling the identification of qPSCs in normal human FFPE pancreatic tissue. Immunohistochemical (IHC), double-IHC, immunofluorescence (IF) and double-IF analyses were carried out using a tissue microarray consisting of cores with normal human pancreatic tissue. Cores with normal human liver served as control. Antibodies directed against adipophilin, α-SMA, CD146, CRBP-1, cytoglobin, desmin, GFAP, nestin, S100A4 and vinculin were examined, with special emphasis on their expression in periacinar cells in the normal human pancreas and perisinusoidal cells in the normal human liver. The immunolabelling capacity was evaluated according to a semiquantitative scoring system. Double-IF of the markers of interest together with markers for other periacinar cells was performed. Moreover, the utility of histochemical stains for the identification of human qPSCs was examined, and their ultrastructure was revisited by electron microscopy. Adipophilin, CRBP-1, cytoglobin and vinculin were expressed in qHSCs in the liver, whereas cytoglobin and adipophilin were expressed in qPSCs in the pancreas. Adipophilin immunohistochemistry was highly dependent on the preanalytical time interval (PATI) from removal of the tissue to formalin fixation. Cytoglobin, S100A4 and vinculin were expressed in periacinar fibroblasts (FBs). The other examined markers were negative in human qPSCs. Our data indicate that cytoglobin and adipophilin are markers of qPSCs in the normal human pancreas. However, the use of adipophilin as a qPSC marker may be limited due to its high dependence on optimal PATI. Cytoglobin, on the other hand, is a sensitive marker for qPSCs but is expressed in FBs as well.

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Acknowledgements

This study was supported by Aase and Ejnar Danielsen’s Foundation (Grant No. 10-001452), The Foundation of 17.12.1981 (Grant No. 19024005), Karen S. Jensens Grant (Grant No. 27-A1433), University of Southern Denmark Faculty Scholarship, Odense University Hospital Free Research Fund and Odense University Hospital Ph.D. stipend (Grant Nos. 29-A1500, 22-A1133 and 1032). The authors express their gratitude to Professor Norifumi Kawada, Osaka City University, Osaka, Japan, for the gift of mono- and polyclonal cytoglobin antibodies. At our department, we would like to thank senior histotechnologist, project coordinator Ole Nielsen as well as histotechnologists Lisbet Mortensen and Lone Christiansen for their assistance with the IHC and d-IHC stainings. We would also like to thank histotechnologists Karin T. Siemonsen and Susan Bøgebjerg for their assistance with the EM analyses. Moreover, we are grateful to Professor Henrik Daa Schrøder, for fruitful discussions during the progress of this project.

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Correspondence to Sönke Detlefsen.

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Nielsen, M.F.B., Mortensen, M.B. & Detlefsen, S. Identification of markers for quiescent pancreatic stellate cells in the normal human pancreas. Histochem Cell Biol 148, 359–380 (2017). https://doi.org/10.1007/s00418-017-1581-5

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  • DOI: https://doi.org/10.1007/s00418-017-1581-5

Keywords

  • Pancreas
  • Pancreatic stellate cells
  • Hepatic stellate cells
  • Adipophilin
  • Cytoglobin
  • S100A4