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Innervation of the proximal human biliary tree

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Abstract

The autonomic nervous system plays a role in a variety of liver regenerative and metabolic functions, including modulating bile secretion and cholangiocyte and hepatobiliary progenitors of the canals of Hering. However, the nature and location of nerves which link to the proximal biliary tree have remained uncertain. We investigate the anatomic relationship of nerves to the proximal biliary tree including the putative stem/progenitor cell niche of the canal of Hering. Using double immunostaining (fluorescence, histochemistry) to highlight markers of cholangiocytes (biliary-type keratins), nerves (S100, neurofilament protein, PGP9.5, tyrosine hydroxylase), and stellate cells (CRBP-1), we examined sections from normal adult livers from autopsy or surgical resections. There is extensive contact between nerves and interlobular bile ducts, bile ductules, and canals of Hering (CoH). In multiple serial sections from 4 normal livers, biliary-nerve contacts were seen in all of these structures and were more common in the interlobular bile ducts (78/137; 57%) than in the ductules and CoH (95/294; 33%) (p < 0.001). Contacts appear to consist of nerves in juxtaposition to the biliary basement membrane, though crossing through basement membrane to interface directly with cholangiocytes is also present. These nerves are positive for tyrosine hydroxylase and are, thus, predominately adrenergic. Electron microscopy confirms nerves closely approximating ductules. Nerve fiber–hepatic stellate cell juxtaposition is observed but without stellate cell approximation to cholangiocytes. We present novel findings of biliary innervation, perhaps mediated in part, by direct cholangiocyte-nerve interactions. The implications of these findings are protean for studies of neuromodulation of biliary physiology and hepatic stem/progenitor cells.

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Abbreviations

HSPC:

Hepatic stem/progenitor cells

PBS:

Proximal biliary structures

CoH:

Canal of Hering

NF:

Neurofilament protein

TH:

Tyrosine hydroxylase

HSC:

Hepatic stellate cell

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Acknowledgments

We gratefully acknowledge Dr. Liliane Dubuisson (SERCOMI, University Bordeaux 2, France) for her help in electron microscopic observation and Mr. Zong-Shi Wang (Histology, Dept. of Pathology, Beth Israel Medical Center, New York, NY, USA) for his careful preparation of serial tissue sections.

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Author notes

  1. Dina G. Tiniakos and Neil D. Theise are the Co-Senior Authors

Authors and Affiliations

  1. Department of Pathology, Morton Plant Hospital, Tampa, FL, USA

    Antonela Zanchi

  2. Department of Surgical Pathology and Laboratory Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Jason Reidy

  3. IBM Watson Health, Cambridge, MA, USA

    Henry J. Feldman

  4. BioDigital, Inc., New York, NY, USA

    John Qualter

  5. Department of Pathology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands

    Annette S. Gouw

  6. Department of Pathology, New York University School of Medicine, New York, NY, USA

    Jon Osbeck & Neil D. Theise

  7. Department of Biological and Environmental Sciences, Troy University, Troy, AL, USA

    Alex Kofman

  8. BaRITOn Bordeaux Research in Translational Oncology, Univ Bordeaux, INSERM UMR1053, Bordeaux, F-33000, France

    Charles Balabaud & Paulette Bioulac-Sage

  9. Department of Pathology, Aretaieion Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece

    Dina G. Tiniakos

  10. Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, William Leech Building, 4th Floor, Room M4-143, Newcastle upon Tyne, NE2 4HH, UK

    Dina G. Tiniakos

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  1. Antonela Zanchi
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Contributions

AZ: experiments and procedures, data analysis, JR: experiments and procedures, HJF: experiments and procedures, data analysis, manuscript preparation, JQ: experiments and procedures, ASG: study design and concept, manuscript preparation, JO: experiments and procedures, AK: experiments and procedures, CB: study design and concept, experiments and procedures, PB-S: study design and concept, data analysis, manuscript preparation, DGT: study design and concept, experiments and procedures, data analysis, manuscript preparation, NDT: study design and concept, experiments and procedures, data analysis, manuscript preparation

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Correspondence to Dina G. Tiniakos.

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Zanchi, A., Reidy, J., Feldman, H.J. et al. Innervation of the proximal human biliary tree. Virchows Arch 477, 385–392 (2020). https://doi.org/10.1007/s00428-020-02761-4

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  • DOI: https://doi.org/10.1007/s00428-020-02761-4

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