Abnormal mitosis in hypertetraploid cells causes aberrant nuclear morphology in association with H2O2-induced premature senescence

Abstract

Aberrant nuclear morphology, such as nuclei with irregular shapes or fragmented nuclei, is often observed in senescent cells, but its biological significance is not fully understood. My previous study showed that aberrant nuclear morphology in senescent human fibroblasts is attributable to abnormal mitosis in later passages. In this study, the production of abnormal nuclei in association with premature senescence was investigated. Premature senescence was induced by brief exposure of human fibroblasts to hydrogen peroxide (H 2O2), and mitosis was observed by time-lapse microscopy. In addition, cell cycle and nuclear morphology after exposure to H 2O2 were also analyzed using a laser scanning cytometer. Time-lapse analysis revealed that the induction of premature senescence caused abnormal mitoses, such as mitotic slippage or incomplete mitosis, especially in later days after H2O2 exposure and often resulted in abnormal nuclear morphology. Analysis by laser scanning cytometer showed significantly higher frequency of abnormal cells with deformed nuclei and abnormal mitotic cells with misaligned chromosomes in a hypertetraploid subpopulation. These results suggest that unstable hypertetraploid cells, formed in association with H2O2-induced premature senescence, cause abnormal mitosis that leads to aberrant nuclear morphology. © 2008 International Society for Advancement of Cytometry.