Cell cycle control of β-cell replication in the prenatal and postnatal human pancreas.
β-Cell regeneration declines with aging, but the molecular mechanisms controlling β-cell replication in humans are not well understood. We compared the expression of selected cell cycle proteins in prenatal and adult tissue and examined the association of these proteins with β-cell replication. Pancreatic tissue from a total of 20 human fetuses and adults was stained for Ki67, cyclin D3, p16 and p27, and insulin. The β-cellular expression of these cell cycle proteins was determined. The frequency of β-cell replication was lower in adult compared with prenatal β-cells (<0.5 vs. 3.4 ± 0.5%, respectively; P < 0.0001). p16 was sporadically expressed in prenatal β-cells (8.0 ± 1.1%) but highly enriched in adult β-cells (63.1 ± 5.2%, P < 0.0001). Likewise, the expression of p27 was much lower in prenatal β-cells (1.7 ± 0.4 vs. 44.1 ± 5.4%, respectively, P < 0.0001), and cyclin D3 expression increased from 24.2 ± 4.1 to 47.25 ± 5.0%, respectively (P < 0.001), with aging. The expression of all three proteins was significantly correlated with each other (P < 0.01 and r > 0.75, respectively). The strong expression of cyclin D3 in adult human β-cells and its correlation to p27 and p16 suggest a positive role in human β-cell cycle regulation. p16 and p27 appear to restrict β-cell replication with aging. The age dependency of cell cycle regulation in human β-cells might explain the reduced β-cell regeneration in adult humans.
Department of Medicine I, St. Josef-Hospital, Ruhr-University of Bochum, Gudrunstr. 56, 44791 Bochum, Germany.
Christina U
CU
Köhler
Marvin
M
Olewinski
Andrea
A
Tannapfel
Wolfgang E
WE
Schmidt
Helga
H
Fritsch
Juris J
JJ
Meier
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002455:Cell Division; D056743:Cyclin D3 / Q000378:metabolism; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D005260:Female; D005865:Gestational Age; D006801:Humans; D007150:Immunohistochemistry; D007328:Insulin / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000166:cytology* / Q000378:metabolism*; D019394:Ki-67 Antigen / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D010179:Pancreas / Q000166:cytology / Q000196:embryology* / Q000254:growth & development* / Q000378:metabolism
C534696:CCND3 protein, human; D018797:Cell Cycle Proteins; D056743:Cyclin D3; D019941:Cyclin-Dependent Kinase Inhibitor p16; D007328:Insulin; D019394:Ki-67 Antigen; D050760:Cyclin-Dependent Kinase Inhibitor p27