RESUMO
AIMS/HYPOTHESIS: An immunohistochemical and genomic analysis of human pancreatic development from 9-23 weeks of fetal age was undertaken to provide a comparative analysis of human and murine islet development. METHODS: Human fetal pancreases obtained at gestational ages 9-23 weeks were processed in parallel for immunohistochemistry and gene expression profiling by Affymetrix microarrays. RESULTS: By 9-11 weeks, the pancreas was made up principally of mesenchymal tissue infiltrated by branched epithelial structures containing scattered hormone-negative neurogenin3-positive endocrine cells. Protoacinar structures emerged by 15-19 weeks, along with clusters of endocrine cells producing either glucagon or insulin. By 20-23 weeks, vascularised islet-like structures appeared. More than 70% of endocrine cells produced a single hormone at any age. Analysis of Ki67 immunoreactivity showed that the replicative rate of endocrine cells was low and suggested that the endocrine expansion was derived from hormone-negative precursors. Insulin, glucagon, somatostatin, ghrelin and pancreatic polypeptide transcripts were present at 9-10 weeks and increased progressively, commensurate with the expansion of endocrine cell volume. The human equivalent of a mouse endocrine secondary transition was not evident, neither in terms of morphology nor in dramatic changes in endocrine-specific transcriptional regulators. By contrast, exocrine genes showed a marked transition at around 11 weeks, associated with a greater than sixfold increase in exocrine gene transcripts. CONCLUSIONS/INTERPRETATION: The observed extension of terminal differentiation of human endocrine tissue into late gestation is in contrast with findings in the mouse. It indicates that the human fetal pancreas could provide an abundant islet precursor cell population that could be expanded ex vivo for therapeutic transplantation.