Transcriptomic analysis of pancreatic tissue from humans and mice identifies potential gene signatures and unexplored pathways during progression from acute to chronic pancreatitis.

Background: A comprehensive understanding of the molecular pathogenesis of chronic pancreatitis (CP), a fibroinflammatory disorder of the pancreas, is warranted for the development of targeted therapies. The current study focused on comparing the transcriptomes of pancreatic tissues obtained from patients with CP with those of two rodent models of chemically induced CP to identify dysregulated genes/signaling pathways.

Methods: Pancreatitis was induced in mice using cerulein and L-arginine. Pancreatic tissues were obtained from humans and mice. The RNA was isolated, and the transcriptomes were generated using the GeneChip Human Transcriptome Array 2.0 and Clariom D Mouse Array respectively. Differentially expressed genes with log2-fold changes ≥ +2 and ≤ -2 were considered for functional and signaling pathway enrichment analysis. The expression of NUCB2, which plays a role in β-cell function, was validated by ELISA in acute pancreatitis (AP) and immune cell responses in AP and CP using flow cytometry.

Results: The current study identifies L-arginine-induced CP as a better model for investigating the pathogenesis of human CP, with greater similarity in dysregulated genes (22%), transcription factors (34%) and enriched pathways (58%) compared to cerulein model (2%, 11% and 9%) respectively. Nesfatin-1, encoded by NUCB2, was decreased in patients with AP (12% nondiabetic, 41% post pancreatitis diabetes). The Th1 immune cell response was greater in the patients with AP (44%), whereas Th17 immune response was greater in patients with CP (18%).

Conclusion: Our study highlights potential novel and unexplored pathways involved in inflammation, fibrosis, and pain in CP and paves the way for testing them as putative drug targets using a severe disease model.