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 lesionislet 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. Keywords 3D pancreatic histology . Human islet . Intra-islet duct . Islet aggregation . Islet cell neogenesis . Pancreatic intraepithelial neoplasia Abbreviations α-SMA α-Smooth muscle actin CK7 Cytokeratin 7 EUS Endoscopic ultrasound PanIN Pancreatic intraepithelial neoplasia * Shiue-Cheng Tang

Transparent tissue in solid state for solvent-free and antifade 3D imaging

“…This phenomenon is highlighted by the detection of duct-islet cell clusters (Fig. 5k–o and Supplementary Movie 7 ) 33 , 41 . In the A-ha copolymer, the cluster is well preserved and can be identified with glucagon (α-cell), insulin (β-cell), and cytokeratin 7 (CK7, duct cell) staining.…”

“…In clinical tissue analysis, we used the human donor pancreas with low-grade duct lesions (pancreatic intraepithelial neoplasia or PanIN) 32 , 33 to demonstrate the integration of A-ha-based 3D histology with the clinical 2D histology. In Fig.…”

Oncogenic KRAS, Mucin 4, and Activin A‐Mediated Fibroblast Activation Cooperate for PanIN Initiation

“…Human pancreatic specimens with early lesions were obtained from two donors (Table S1 , Supporting Information) with normal HbA1c, amylase, and lipase levels. [ 45 ] Tissue arrays, PA483e and HPan060SC02, with normal pancreas tissues, normal pancreas tissues adjacent to the tumor (NAT), and PDAC tumors were purchased from US Biomax Inc. For MUC4 IHC staining analysis, it was utilized 13 normal pancreas and NAT tissues, which do not contain PanINs, as well as 44 stage I/II PDAC samples. The relevant patient information had been included in Figure S5A (Supporting Information).…”

“…Once confirmed, multiplex signals from the same microenvironment were further acquired from adjacent sections via standard immunohistochemistry (4 µm sections; Bond Polymer detection kit, Leica Biosystems #DS9800/DS9390) and 3D histology (350 µm sections) as described previously. [ 45 ]…”