β-cell development and turnover during prenatal life in humans

Abstract

Introductionβ-cell regeneration is an area under active investigation for the future treatment of diabetes, but little is known about the patterns and dynamics of prenatal β-cell development in humans. In particular, the quantitative changes in β-cell mass in the developing pancreas have not been elucidated in detail. We addressed the following questions in prenatal humans: i) what is the timing of β-cell occurrence and islet growth? ii) What are the dynamics of β-cell replication and apoptosis?MethodsPancreatic tissue was obtained from 65 human embryos and foetuses aged between 8 weeks post conception (p.c.) and birth. Sections were stained for insulin, glucagon, Ki67 (proliferation marker), TUNEL (apoptosis marker) and CD31 (blood vessel marker), and morphometric analyses were performed.Resultsβ-cells were detected from gestational week 9 onward, whereas glucagon expression was detected already at week 8. The fractional β-cell area of the pancreas increased in a linear fashion until birth (r=0.60, P<0.001). The first endocrine cells were found within or adjacent to the primitive ductal epithelium. β-cell replication was readily detected in the newly forming islets already starting at week 9 p.c. (average frequency 2.8±0.4%). A small percentage of cells co-expressed insulin and glucagon during the early foetal period. There was a close relationship between the development of endocrine islets and blood vessels during all stages of prenatal pancreas development suggesting a possible interaction between both cell types. The frequency of β-cell apoptosis was relatively high throughout all ages (1.5±0.3%).Conclusionsβ-cell differentiation in humans occurs from week 9 p.c. onward. The first endocrine cells are closely associated with the ductal epithelium suggesting differentiation from precursor cells. High rates of β-cell replication suggest that this mechanism plays an important role in the prenatal expansion of β-cell mass.