Local islet remodelling associated with duct lesion–islet complex in adult human pancreas

Abstract

Aims/hypothesis

Islets are thought to be stably present in the adult human pancreas to maintain glucose homeostasis. However, identification of the pancreatic intraepithelial neoplasia (PanIN)–islet complex in mice and the presence of PanIN lesions in adult humans suggest that similar remodelling of islet structure and environment may occur in the human pancreas. To identify islet remodelling in a clinically related setting, we examine human donor pancreases with 3D histology to detect and characterise the human PanIN–islet complex.

Methods

Cadaveric donor pancreases (26–65 years old, n = 10) were fixed and sectioned (350 μm) for tissue labelling, clearing and microscopy to detect local islet remodelling for 3D analysis of the microenvironment. The remodelled microenvironment was subsequently examined via microtome-based histology for clinical assessment.

Results

In nine pancreases, we identified the unique peri-lobular islet aggregation associated with the PanIN lesion (16 lesion–islet complexes detected; size: 3.18 ± 1.34 mm). Important features of the lesion–islet microenvironment include: (1) formation of intra-islet ducts, (2) acinar atrophy, (3) adipocyte association, (4) inflammation (CD45+), (5) stromal accumulation (α-SMA+), (6) increase in Ki-67 proliferation index but absence of Ki-67+ alpha/beta cells and (7) in-depth and continuous duct–islet cell contacts, forming a cluster. The duct–islet cell cluster and intra-islet ducts suggest likely islet cell neogenesis but not replication.

Conclusions/interpretation

We identify local islet remodelling associated with PanIN–islet complex in the adult human pancreas. The tissue remodelling and the evidence of inflammation and stromal accumulation suggest that the PanIN–islet complex is derived from tissue repair after a local injury.

Graphical abstract

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Data availability

The images and datasets generated during the current study are available from the corresponding author on reasonable request.

Abbreviations

α-SMA:

α-Smooth muscle actin

CK7:

Cytokeratin 7

EUS:

Endoscopic ultrasound

PanIN:

Pancreatic intraepithelial neoplasia

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Acknowledgements

The authors are grateful for the support from the confocal imaging core in National Tsing Hua University, which is sponsored by the Ministry of Science and Technology, Taiwan (MOST 108-2731-M-007-001).

Authors’ relationships and activities

The authors declare that there are no relationships or activities that might bias, or be perceived to bias, their work.

Funding

This work was supported in part by grants from Taiwan Academia Sinica (AS-107-TP-L15) to YWT and SCT, Taiwan Ministry of Science and Technology (MOST 108-2321-B-002-009) to YWT, and Taiwan National Health Research Institutes (NHRI-EX109-10922EI and NHRI-EX110-10922EI) and MOST (106-2314-B-007-004-MY2 and 108-2314-B-007-006-MY2) to SCT.

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Authors

Contributions

All authors contributed to the study concept and design; Y-WT, T-CC, C-YL, C-CC and Y-MJ contributed to human pancreas acquisition and preparation; H-JC, S-JP, M-HC, Y-HC, F-TH, and S-CT contributed to 3D multiplex histology and image presentation; and Y-WT and S-CT contributed to drafting of the manuscript. Y-WT and S-CT obtained funding. All authors contributed to data analysis and interpretation of data, revised the manuscript critically for intellectual content, and approved the final version of the manuscript. S-CT 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.

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Correspondence to Shiue-Cheng Tang.

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Supplementary Information

ESM

(PDF 27943 kb)

ESM Video 1 (related to Fig. 1)

In-depth, high-definitional presentation of PanIN in the PanIN–islet complex. This video uses a side-by-side illustration to compare the lesion in the H&E micrograph (left) and the 3D image stack (right, in-depth recording of fluorescence and transmitted light signals). The H&E micrograph provides the ground-truth tissue information to identify the PanIN-1B lesion. Its feature is truthfully presented in the recording (right), confirming the 3D approach of tissue imaging. Magenta, glucagon; green, CK7; white, nuclei. (MP4 8996 kb)

ESM Video 2 (related to Fig. 4)

Lymphangiogenesis associated with the PanIN–islet complex. Left: in-depth recording of lymphatic vessels (green, D2-40) around duct lesions and aggregated islets (magenta, glucagon; white, nuclei). Right: 3D projection of lymphatic vessels in the microenvironment.(MP4 6331 kb)

ESM Video 3 (related to Fig. 5)

Peri- and intra-islet cell proliferation in the PanIN–islet microenvironment. Left: gross view of aggregated islets (3D projection and 2D image). Right: magnified examination of Ki-67+ nuclei. The Ki-67+ nuclei are identified inside and around the islet but not enclosed by the glucagon (magenta) or insulin (blue) signals. Blue, insulin; magenta, glucagon; green, nuclei; yellow: Ki-67. In the first half of the video (00:00-00:10), the overlap of yellow (Ki-67) and green (nuclear staining) signals is used to detect and confirm the cell proliferation. In the second half (00:11-00:21), the same microenvironment is displayed without the green signals to emphasize the locations of Ki-67+ nuclei. (MP4 8919 kb)

ESM Video 4 (related to Fig. 5)

Cell proliferation in the PanIN–islet microenvironment: in-depth recording and projection. Upper panel: in-depth recording of Ki-67+ nuclei. Lower panel: projection of Ki-67+ signals to register their locations. Blue, insulin; magenta, glucagon; green, nuclei; yellow: Ki-67. Sixteen Ki-67+ nuclei are identified in this view. The numbers at the lower panel indicate their order of appearance in the video. In particular, number 1, 2, 4, 5, 6, 13, and 14 are adjacent to the glucagon+ (magenta) or insulin+ (blue) cells but not enclosed by the two endocrine markers. (MP4 7967 kb)

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Tien, YW., Chien, HJ., Chiang, TC. et al. Local islet remodelling associated with duct lesion–islet complex in adult human pancreas. Diabetologia (2021). https://doi.org/10.1007/s00125-021-05504-5

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Keywords

  • 3D pancreatic histology
  • Human islet
  • Intra-islet duct
  • Islet aggregation
  • Islet cell neogenesis
  • Pancreatic intraepithelial neoplasia