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Single cell RNA-seq defines novel heterogeneity within the pancreatic ductal tree

ABSTRACT: Single cell RNA-seq defines novel heterogeneity within the pancreatic ductal tree

PROVIDER: PRJNA668391 | ENA |

REPOSITORIES: ENA

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			Action	DRS
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	SRR12804316_1.fastq.gz	Fastqsanger.gz
	SRR12804316_2.fastq.gz	Fastqsanger.gz
	SRR12804317_1.fastq.gz	Fastqsanger.gz
	SRR12804317_2.fastq.gz	Fastqsanger.gz

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Single cell RNA-seq defines novel heterogeneity within the pancreatic ductal tree

Project description:Lineage tracing using genetically engineered mouse models has become an essential tool for investigating cell-fate decisions of progenitor cells and biology of mature cell types, with respect to physiology and disease progression. 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 isolated duct cells within the murine pancreas using the DBA lectin sorting strategy that labels all pancreatic duct cell types. Our data contest the paradigm suggested by previous single cell studies that murine pancreatic duct cells are homogenous. We describe an epithelial mesenchymal transitory axis among our two subpopulations of pancreatic duct cells and identify SPP1 as a regulator of this phenotype and human duct cell de-differentiation. Our results further define functional heterogeneity of 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 disease progression and establish a comprehensive road map of murine pancreatic duct cell, pancreatobiliary cell, and intrapancreatic bile duct cell homeostasis.

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Project description:Pancreatic ducts form an intricate network of tubules that secrete bicarbonate and drive acinar secretions into the duodenum. This network is formed by centroacinar cells, terminal, intercalated, intracalated ducts, and the main pancreatic duct. Ductal heterogeneity at the single-cell level has been poorly characterized. Here, we used scRNA-seq to comprehensively characterize mouse ductal heterogeneity at single-cell resolution of the entire ductal epithelium from centroacinar cells to the main duct. Moreover, we used organoid cultures, injury models and pancreatic tumor samples to interrogate the role of novel ductal populations in pancreas regeneration and exocrine pathogenesis. In our study, we have identified the coexistence of 15 ductal populations within the healthy pancreas and characterized their organoid formation capacity and endocrine differentiation potential. Cluster isolation and subsequent culturing let us identify ductal cell populations with high organoid formation capacity and endocrine and exocrine differentiation potential in vitro, including Wnt-responsive-population, ciliated-population and FLRT3+ cells. Moreover, we have characterized the location of these novel ductal populations in healthy pancreas, chronic pancreatitis and tumor samples, hightlihgting a putative role of WNT-responsive, IFN-responsive and EMT-populations in pancreatic exocrine pathogenesis as their expression inceases in chronic pancreatitis and PanIN lesions. In light of our discovery of previously unidentified ductal populations, we unmask the potential roles of specific ductal populations in pancreas regeneration and exocrine pathogenesis.

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