Abstract
We have previously demonstrated that the pancreas can recover from chronic pancreatitis (CP) lesions in the cerulein-induced mouse model. To explore how pancreatic recovery is achieved at the molecular level, we used RNA-sequencing (seq) and profiled transcriptomes during CP transition to recovery. CP was induced by intraperitoneally injecting cerulein in C57BL/6 mice. Time-matched controls (CON) were given normal saline. Pancreata were harvested from mice 4 days after the final injections (designated as CP and CON) or 4 weeks after the final injections (designated as CP recovery (CPR) and control recovery (CONR)). Pancreatic RNAs were extracted for RNA-seq and quantitative (q) PCR validation. Using RNA-seq, we identified a total of 3,600 differentially expressed genes (DEGs) in CP versus CON and 166 DEGs in CPR versus CONR. There are 132 DEGs overlapped between CP and CPR and 34 DEGs unique to CPR. A number of selected pancreatic fibrosis-relevant DEGs were validated by qPCR. The top 20 gene sets enriched from DEGs shared between CP and CPR are relevant to extracellular matrix and cancer biology, whereas the top 10 gene sets enriched from DEGs specific to CPR are pertinent to DNA methylation and specific signaling pathways. In conclusion, we identified a distinct set of DEGs in association with extracellular matrix and cancer cell activities to contrast CP and CPR. Once during ongoing CP recovery, DEGs relevant to DNA methylation and specific signaling pathways were induced to express. The DEGs shared between CP and CPR and the DEGs specific to CPR may serve as the unique transcriptomic signatures and biomarkers for determining CP recovery and monitoring potential therapeutic responses at the molecular level to reflect pancreatic histological resolution.
Highlights
Chronic pancreatitis (CP) is a devastating disease characterized by inflammation, fibrosis, and consequent loss of exocrine and endocrine pancreatic function
Chronic pancreatitis was induced in adult male and female mice by cerulein (50 μg/kg, intraperitoneal, 5 hourly injections/day, 3 days/week), and the pancreata were harvested 4 days or 4 weeks after the final injections as previously described and quantified on several major functional analyses [10]
We found respective human homologs of 6 out of 7 genes validated in Quantitative Real-Time PCR (qPCR) assays, including Extracellular Matrix (ECM) genes Col1a2 and Fn1, TGF-beta superfamily and signaling pathway genes transforming growth factor- (Tgf-)beta1, Id3, and Gdf10, and Fgf21
Summary
Chronic pancreatitis (CP) is a devastating disease characterized by inflammation, fibrosis, and consequent loss of exocrine and endocrine pancreatic function. The most common etiology is alcohol consumption, known to increase the risk of CP in a dose-dependent manner and shown to be related to over 50% of CP cases [1,2,3,4,5]. CP imposes large burdens on patients and healthcare systems, as the economic burden of CP in the US is estimated to be over $150 million annually [6]. Patients with CP are at a higher risk of developing type 3c diabetes and pancreatic cancer [7, 8]. Initially recognized as a clinical disease entity in 1946 [9], little to no therapeutic advancement has been made over the past six decades, rendering the treatment primarily supportive
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