Integrated transcriptome profiling of plasma exosomes reveals molecular stratification of exocrine and endocrine disorders and S100A8-mediated cell interactions in chronic pancreatitis.

Exocrine and endocrine disorders and insufficiency are two major harmful pathological processes in chronic pancreatitis (CP) and can lead to steatorrhea and diabetes. However, there is a lack of reliable clinical classification schemes for evaluating the severity of exocrine and endocrine disorders in CP, and the underlying mechanisms are also unclear. In particular, exosome-based liquid biopsy and classification in CP are lacking. Here, we performed transcriptome sequencing on plasma exosomes from CP patients with different degrees of CP severity. Additionally, we analyzed single-cell sequencing data from pancreatic lesions in CP patients to interpret the classification, and an external cohort was established to verify the classification. Ultimately, we established and preliminarily verified a 3-stage classification system to predict steatorrhea and diabetes onset in CP patients based on the expression of 12 miRNAs in plasma exosomes. A publicly-available online tool implementing this classification system was also developed. Further analysis, in combination with single-cell sequencing data from CP mice, identified exosome-derived miR-24-3p and neutrophil S100A8 as pivotal factors in CP progression. Mechanistically, our findings suggest that downregulated exosome-derived miR-24-3p in CP may lead to the upregulation of its target gene, S100A8, in neutrophils, thus promoting CP-related exocrine and endocrine disorders by activating the fibrotic phenotype of pancreatic stellate cells and inducing inflammation in macrophages, leading to the apoptosis of pancreatic β cells. Together, our work provides a novel exosome-based 3-stage classification system for CP and highlights the role of exosomal miR-24-3p and S100A8 in fibrosis and pancreatic β-cell apoptosis.