Single-cell transcriptome analysis defines heterogeneity of the murine pancreatic ductal tree

Abstract

To study disease development, an inventory of an organ's cell types and understanding of physiologic function is paramount. Here, we performed single-cell RNA sequencing to examine heterogeneity of murine pancreatic duct cells, pancreatobiliary cells, and intrapancreatic bile duct cells. We describe an epithelial-mesenchymal transitory axis in our three pancreatic duct subpopulations and identify osteopontin as a regulator of this fate decision as well as human duct cell dedifferentiation. Our results further identify functional heterogeneity within pancreatic duct subpopulations by elucidating a role for geminin in accumulation of DNA damage in the setting of chronic pancreatitis. Our findings implicate diverse functional roles for subpopulations of pancreatic duct cells in maintenance of duct cell identity and disease progression and establish a comprehensive road map of murine pancreatic duct cell, pancreatobiliary cell, and intrapancreatic bile duct cell homeostasis.

Single-Cell Transcriptomic Analysis of the Mouse Pancreas: Characteristic Features of Pancreatic Ductal Cells in Chronic Pancreatitis

“…Compared with Hendley et al’s study [ 45 ], we did not identify the subpopulations of the pancreatic ductal cells; this is considered to be due to the insufficient cell numbers. More recently, Ma et al identified cell populations arising from ADM under conditions of chronic injury by combining lineage tracing and scRNA-seq technology [ 22 ].…”

Transcriptomic-Based Quantification of the Epithelial-Hybrid-Mesenchymal Spectrum across Biological Contexts

“…Next, we plotted the histograms for the EMT scores of various single-cell RNA-seq datasets to decipher the heterogeneity seen along the EMP spectrum across a variety of biological contexts: 1. human embryonic stem-cell-derived progenitor cells differentiating to endoderm (GSE75748) [ 63 ]; 2. human fetal pituitary gland development including progenitors of many endocrine cell types and subtypes (GSE142653) [ 64 ]; 3. cells from different tissues and organs of E9.5 to E11.5 mouse embryos (GSE87038) [ 65 ]; 4. MCF10A cells treated with TGF-β for varying durations and exhibiting a gradual change in their EMT status (PRJNA698642) [ 66 ]; 5. murine pancreatic duct cells with variations along the EMP spectrum (GSE159343) [ 67 ]; 6. EpCAM+ and EpCAM- squamous skin carcinoma cells with varied epithelial and/or mesenchymal features (GSE110357) [ 68 ]; 7. cells from oral cavity tumors/head and neck squamous cell carcinoma (GSE103322) [ 17 ]; 8. human colorectal cancer cell lines and tumors (GSE81861) [ 69 ], and 9. mouse hair follicle stem cells and transit-amplifying cells (GSE90848) [ 70 ].…”

Transcriptomic-based quantification of the epithelial-hybrid-mesenchymal spectrum across biological contexts

“…Next, we plotted the histograms for EMT scores of various single-cell RNA-seq datasets to decipher the heterogeneity seen along the EMP spectrum across a variety of biological contexts: 1. human embryonic stem-cell-derived progenitor cells differentiating to endoderm (GSE75748) (Chu et al, 2016); 2. human fetal pituitary gland development including progenitors of many endocrine cell types and subtypes (GSE142653) (Zhang et al, 2020); 3. cells from different tissues and organs of E9.5 to E11.5 mouse embryos (GSE87038) (Dong et al, 2018); 4. MCF10A cells treated with TGF-β for varying durations and exhibiting a gradual change in their EMT status (PRJNA698642) (Deshmukh et al, 2021); 5. murine pancreatic duct cells with variations along the EMP spectrum (GSE159343) (Hendley et al, 2021); 6. EpCAM+ and EpCAM-squamous skin carcinoma cells with varied epithelial and/or mesenchymal features (GSE110357) (Pastushenko et al, 2018); 7. cells from oral cavity tumors/head and neck squamous cell carcinoma (GSE103322) (Puram et al, 2017); 8. human colorectal cancer cell lines and tumors (GSE81861) (Li et al, 2017), and; 9. mouse hair follicle stem cells and transit-amplifying cells (GSE90848) (Yang et al, 2017).…”