Islet morphogenesis and stem cell markers.

Abstract

The mechanism of islet neogenesis remains poorly understood, despite its potential applications in regenerative or replacement therapies for the treatment of insulin-dependent diabetes. During fetal development of the mouse or rat, the majority of islet cells are formed in late gestation (E18-21) by the process of neogenesis from precursor cells. The precursor cells are organized as ducts that actively proliferate and express high levels of specific cytokeratin (CK) proteins. Transitional cells coexpressing islet hormones and CK are frequent and disappear shortly after birth, to reappear only in conditions in which pancreas or islet regeneration has been induced. Islet morphogenesis is thought to operate mainly through the budding of islet cells from ducts, followed by their migration away from the duct to form clusters. Single islet cells are indeed frequent in the fetal and regenerating pancreas, but they also occur in normal tissue, especially in the human pancreas. A different neogenic mechanism, observed in the fetal rat, consists in the proliferation of ductal cells resulting in large aggregates. Starting from the middle of the aggregate, cells differentiate into islet cells and gradually lose their proliferative activity and other ductal characteristics. In adult pancreas, islets are in close contact with at least one duct or ductule. Such a direct duct-islet axis becomes even more evident in regeneration models, such as duct ligation. In these models, a metaplastic transformation of the exocrine pancreas to so-called pseudoductal complexes is seen. Surviving exocrine cells acquire a metaplastic phenotype, which resembles the fetal protodifferentiated state. They start to express CK, the beta-cell transcription factor Pdx1, the neuroendocrine/islet cell markers PGP9.5 and the CCKB receptor for gastrin, and they show pronounced proliferative activity and islet neogenesis. We hypothesize that these de-differentiated or metaplastic exocrine cells (acinar and ductal), acquire a multipotential state and can serve as islet precursors.