Accelerated telomere shortening and senescence in human pancreatic islet cells stimulated to divide in vitro.
Widespread application of beta-cell replacement strategies for diabetes is dependent upon the availability of an unlimited supply of cells exhibiting appropriate glucose-responsive insulin secretion. Therefore, a great deal of effort has been focused on understanding the factors that control beta-cell growth. Previously, we found that human beta-cell-enriched islet cultures can be stimulated to proliferate, but expansion was limited by growth arrest after 10-15 cell divisions. Here, we have investigated the mechanism behind the growth arrest. Our studies, including analyses of the expression of senescence-associated beta-galactosidase, p16(INK4a) levels, and telomere lengths, indicate that cellular senescence is responsible for limiting the number of cell divisions that human beta-cells can undergo. The senescent phenotype was not prevented by retroviral transduction of the hTERT gene, although telomerase activity was induced. These results have implications for the use of primary human islet cells in cell transplantation therapies for diabetes.
Halvorsen
T L
TL
Center for Molecular Genetics, University of California San Diego School of Medicine, San Diego, California 92093-0634, USA.
Beattie
G M
GM
Lopez
A D
AD
Hayek
A
A
Levine
F
F
D000293:Adolescent; D000328:Adult; D002352:Carrier Proteins / Q000032:analysis; D018797:Cell Cycle Proteins; D002455:Cell Division; D002478:Cells, Cultured; D016922:Cellular Senescence; D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16; D004268:DNA-Binding Proteins; D003922:Diabetes Mellitus, Type 1 / Q000601:surgery; D004790:Enzyme Induction; D005260:Female; D006801:Humans; D007515:Islets of Langerhans / Q000201:enzymology / Q000648:ultrastructure*; D008297:Male; D008875:Middle Aged; D012313:RNA; D019098:Telomerase / Q000096:biosynthesis / Q000235:genetics; D016615:Telomere / Q000648:ultrastructure*; D014162:Transfection; D025521:Tumor Suppressor Proteins; D001616:beta-Galactosidase / Q000032:analysis
C493966:CDKN2B protein, human; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16; D004268:DNA-Binding Proteins; D025521:Tumor Suppressor Proteins; C422952:telomerase RNA; D012313:RNA; D019098:Telomerase; D001616:beta-Galactosidase