Activated Human Pancreatic Stellate Cells SignatureCommunication in Type 1 Diabetes.

BACKGROUND

Type 1 diabetes (T1D) is an autoimmune disease resulting in the destruction of pancreatic β-cells leading to insulin deficiency and hyperglycemia. Single cell transcriptomic analysis of human islets demonstrated profound β-cell changes and revealed heterogeneity in endocrine and exocrine cells in T1D. Pancreatic stellate cells (PSCs), the resident mesenchymal cells of the pancreas, regulate extracellular matrix homeostasis and drive fibrosis in aging, pancreatitis, and pancreatic cancer. By secreting cytokines and growth factors, PSCs contribute to local immunity and inflammation that affect pancreatic exocrine and endocrine functions. However, cell-cell communication from single cell transcriptomics analyzing the role of PSCs in T1D has not been explored.

METHODS

We analyzed single-cell RNA sequencing data from human pancreatic islets of 20 donors with and without T1D from the Human Pancreas Analysis Program database using the CellChat R package, focusing on activated-PSCs (aPSCs) signaling pathways. In addition, we performed aPSCs differential expression gene and gene set enrichment analyses.

RESULTS

CellChat analysis revealed aPSCs demonstrated major changes increasing the number and strength of cellular communications in T1D compared to control pancreata. Signaling pathways upregulated in cell-to-cell communication involving aPSCs include TGFB, FGF, CXCL, ANGPTL, and NGF, and their respective ligands TGFB1/3, FGF7, CXCL12, ANGPTL4 and NGF. In contrast, PTN signaling from aPSCs was blunted in T1D.

CONCLUSIONS

Our study revealed novel intercellular communication signatures involving aPSCs in T1D. Identification of the changes in cellular communication between aPSCs and other cells in T1D suggest a role in T1D pathogenesis or progression which might lead to the development of novel therapeutics.