PanIN-associated pericyte, glial, and islet remodeling in mice revealed by 3D pancreatic duct lesion histology

Pei Yu Lin, Shih Jung Peng, Chia Ning Shen, Pankaj J. Pasricha, Shiue Cheng Tang

Research output: Contribution to journalArticlepeer-review

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 KrasG12D 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 KrasG12D-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.

Original languageEnglish (US)
Pages (from-to)G412-G422
JournalAmerican Journal of Physiology - Gastrointestinal and Liver Physiology
Volume311
Issue number3
DOIs
StatePublished - 2016

Keywords

  • 3D histology
  • Kras mutation
  • Optical clearing
  • PanIN-islet complex
  • Pancreatic intraepithelial neoplasia

ASJC Scopus subject areas

  • Physiology
  • Hepatology
  • Gastroenterology
  • Physiology (medical)

Fingerprint Dive into the research topics of 'PanIN-associated pericyte, glial, and islet remodeling in mice revealed by 3D pancreatic duct lesion histology'. Together they form a unique fingerprint.

Cite this