title: PanIN-associated pericyte, glial, and islet remodeling in mice revealed by 3D pancreatic duct lesion histology.
abstract: Pericytes and glial cells are accessory cells of neurovascular networks, which have been reported to participate in scar formation after tissue injury. However, it remains unclear whether similar reactive cellular responses occur in pancreatic intraepithelial neoplasia (PanIN). In this study we developed three-dimensional (3D) duct lesion histology to investigate PanIN and the associated pericyte, glial, and islet remodeling. Transparent mouse pancreata with a Kras(G12D) mutation were used to develop 3D duct lesion histology. Deep-tissue, tile-scanning microscopy was performed to generate panoramic views of the diseased pancreas for global examination of early stage and advanced duct lesion formation. Fluorescence signals of ductal and neurovascular networks were simultaneously detected to reveal associated remodeling. Significantly, in Kras(G12D)-mutant mice, when the low-grade PanINs emerge, duct lesions appear as epithelial buds with perilesional pericyte and glial activation. When PanINs occur in large scale (induced by cerulein injections to the mutant mice), the 3D image data identifies 1) aggregation of PanINs in clusters in space; 2) overexpression of the pericyte marker NG2 in the PanIN microenvironment; and 3) epithelial in-growth to islets, forming the PanIN-islet complexes. Particularly, the PanIN-islet complexes associate with proliferating epithelial and stromal cells and receive substantial neurovascular supplies, making them landmarks in the atrophic lobe. Overall, perilesional pericyte and glial activation and formation of the PanIN-islet complex underline cellular heterogeneity in the duct lesion microenvironment. The results also illustrate the advantage of using 3D histology to reveal previously unknown details of neurovascular and endocrine links to the disease.
authors.affiliation: Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan; Genomics Research Center, Academia Sinica, Taipei, Taiwan;
authors.forename: Pei-Yu
authors.initials: PY
authors.lastname: Lin
authors.affiliation: Institute of Biotechnology, National Tsing Hua University, Hsinchu, Taiwan; Department of Medical Science, National Tsing Hua University, Hsinchu, Taiwan; and.
authors.forename: Shih-Jung
authors.initials: SJ
authors.lastname: Peng
authors.affiliation: Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan; Genomics Research Center, Academia Sinica, Taipei, Taiwan;
authors.forename: Chia-Ning
authors.initials: CN
authors.lastname: Shen
authors.affiliation: Division of Gastroenterology and Hepatology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Pankaj J
authors.initials: PJ
authors.lastname: Pasricha
authors.affiliation: Institute of Biotechnology, National Tsing Hua University, Hsinchu, Taiwan; Department of Medical Science, National Tsing Hua University, Hsinchu, Taiwan; and sctang@life.nthu.edu.tw.
authors.forename: Shiue-Cheng
authors.initials: SC
authors.lastname: Tang
mesh_terms: D000818:Animals; D002278:Carcinoma in Situ / Q000473:pathology*; D021441:Carcinoma, Pancreatic Ductal / Q000473:pathology*; D015972:Gene Expression Regulation, Neoplastic; D007515:Islets of Langerhans / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D009457:Neuroglia / Q000502:physiology*; D010179:Pancreas / Q000473:pathology*; D020286:Pericytes / Q000502:physiology*
keywords: 3D histology; KrasG12D mutation; PanIN-islet complex; optical clearing; pancreatic intraepithelial neoplasia