Single-cell sequencing identifies broad patterns of cellular heterogeneity in E14.5 murine pancreas. Despite previous work focused on the formation of the endocrine compartment, the precise timing and coordination of lineage decisions are not completely understood. Gastrin+ cells have also been recently described 3. Within the trunk domain, induction of Neurogenin 3 ( Ngn3) expression defines the cells that will differentiate into one of five endocrine lineages: alpha, beta, delta, gamma, or epsilon cells, marked by expression of the hormones Glucagon (Gcg), Insulin (Ins), Somatostatin (Sst), Pancreatic polypeptide (PP), or Ghrelin (Ghrl), respectively 2. Further epithelial lineage diversification continues with the specification of Pdx1+ cells into tip and trunk domains by E12 and progresses to the restriction of tip cells to a digestive enzyme-producing acinar fate and of trunk cells to either a ductal or endocrine cell fate 1. These Pdx1+ cells evaginate into a cap of surrounding mesenchymal cells around embryonic day 9 (E9), proliferate, and begin the process of branching morphogenesis. In the mouse, all known epithelial lineages of the pancreas derive from a small field of epithelial precursor cells within the foregut endoderm specified by the expression of Pancreatic duodenal transcription factor 1 ( Pdx1) (Fig.
Pancreatic organogenesis is a complex and dynamic process that ultimately results in the generation of multiple cell lineages that perform the functions of the mature organ: the regulation of glucose homeostasis by the endocrine compartment and the production of digestive enzymes by the exocrine compartment. This work establishes a roadmap of pancreatic development and demonstrates the broad utility of this approach for understanding lineage dynamics in developing organs. Further, we identify candidate transcriptional regulators along the differentiation trajectory of this population toward the alpha or beta cell lineages. Within the epithelium, we find a previously undescribed endocrine progenitor population, as well as an analogous population in both human fetal tissue and human embryonic stem cells differentiating toward a pancreatic beta cell fate. We identify previously underappreciated cellular heterogeneity of the developing mesenchyme and reconstruct potential lineage relationships among the pancreatic mesothelium and mesenchymal cell types. Here, we profile the cell types within the epithelial and mesenchymal compartments of the murine pancreas across developmental time using a combination of single-cell RNA sequencing, immunofluorescence, in situ hybridization, and genetic lineage tracing. Organogenesis requires the complex interactions of multiple cell lineages that coordinate their expansion, differentiation, and maturation over time.
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