Early pattern of differentiation in the human pancreas.

In the early human embryonic/fetal pancreas, we studied 1) the ontogenetic pattern of the endocrine cells and the evolution of the endocrine mass, and 2) the morphogenetic pattern of development and, more precisely, the complex relationship of the epithelial mass with the surrounding mesenchyme. We studied 15 pancreases between 7 and 11 weeks of development (WD) by double immunohistochemistry. Epithelial cells in these pancreatic anlage were detected by cytokeratin staining, and differentiated endocrine cells were detected by insulin, glucagon, somatostatin, and pancreatic polypeptide staining. Proliferation was quantified using a nuclear marker, the Ki-67 antibody. At this early stage, the pancreas is made up of an epithelial mass composed of central ducts intermingled with a loose mesenchyme and peripheral ducts surrounded by a dense peripancreatic mesenchyme. Hormone-containing cells appear in the epithelium at 8 WD. Newly differentiated endocrine cells coexpress insulin, glucagon, and somatostatin; endocrine differentiation starts within the central ducts of the epithelial mass, at a distance from the dense peripancreatic surrounding mesenchyme. The fraction of the primitive endocrine cells undergoing proliferation is low (5% of the insulin cells at 8 WD, 3% at 11 WD), which is in favor of massive differentiation as the major mechanism for increasing endocrine mass. By contrast, the nonendocrine epithelial cells have a higher rate of proliferation; the epithelial cells in contact with the dense peripancreatic surrounding mesenchyme show more proliferation activity than those within the central part of the epithelial mass (at 11 WD, labeling index: periphery 65% vs. center 15%, P < 0.001). In conclusion, the patterns of endocrine differentiation and epithelial proliferation observed within the human pancreas early in development suggest that the mesenchyme plays a role in these phenomena.