Beta-cell development and turnover during prenatal life in humans.
BACKGROUND
beta-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 beta-cell development in humans. In particular, the quantitative changes in beta-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 beta-cell occurrence and islet growth? ii) What are the dynamics of beta-cell replication and apoptosis?


METHODS
Pancreatic 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.


RESULTS
beta-cells were detected from gestational week 9 onward, whereas glucagon expression was detected already at week 8. The fractional beta-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. beta-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 beta-cell apoptosis was relatively high throughout all ages (1.5+/-0.3%).


CONCLUSIONS
beta-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 beta-cell replication suggest that this mechanism plays an important role in the prenatal expansion of beta-cell mass.
Meier
Juris J
JJ
Department of Medicine I, St Josef-Hospital, Ruhr-University of Bochum, Gudrunstrasse 56, Bochum 44791, Germany. juris.meier@rub.de
Köhler
Christina U
CU
Alkhatib
Bacel
B
Sergi
Consolato
C
Junker
Theresa
T
Klein
Harald H
HH
Schmidt
Wolfgang E
WE
Fritsch
Helga
H
D017209:Apoptosis / Q000502:physiology; D002454:Cell Differentiation / Q000502:physiology; D002455:Cell Division / Q000502:physiology; D049109:Cell Proliferation; D005260:Female; D005934:Glucagon / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D007328:Insulin / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000378:metabolism*; D007515:Islets of Langerhans / Q000196:embryology* / Q000378:metabolism; D008297:Male; D008856:Microscopy, Fluorescence; D010179:Pancreas / Q000196:embryology* / Q000378:metabolism*
D007328:Insulin; D005934:Glucagon