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Early loss of proliferative potential of human peritoneal mesothelial cells in culture: the role of p16^INK4a-mediated premature senescence

Krzysztof Ksiek,¹ Katarzyna Piwocka,² Agnieszka Brzeziska,² Ewa Sikora,² Maciej Zabel,³ Andrzej Brborowicz,¹ Achim Jörres,⁴ and Janusz Witowski^1,4

¹Department of Pathophysiology and ³Department of Histology and Embryology, University Medical School, Pozna; and ²Laboratory for Molecular Bases of Aging, Nencki Institute of Experimental Biology, Warsaw, Poland; and ⁴Department of Nephrology and Medical Intensive Care, Charité-Universitätsmedizin Berlin, Campus Virchow-Klinikum, Berlin, Germany

Submitted 6 September 2005 ; accepted in final form 25 October 2005

Much has been learned about the mechanisms underlying cellular senescence. The pathways leading to senescence appear to vary, depending on the cell type and cell culture conditions. In this respect, little is known about senescence of human peritoneal mesothelial cells (HPMC). Previous studies have significantly differed in the reported proliferative lifespan of HPMC. Therefore, in the present study, we have examined how HPMC enter state of senescence under conditions typically used for HPMC culture. HPMC were isolated from omentum and grown into senescence. The cultures were assessed for the growth rate, the presence of senescence markers, activation of cell-cycle inhibitors, and the oxidative stress. HPMC were found to reach, on average, six population doublings before senescence. The terminal growth arrest was associated with decreased expression of Ki67 antigen, increased percentage of cells in the G1 phase, reduced early population doubling level cDNA-1 mRNA expression, and the presence of senescence-associated -galactosidase. Compared with early-passage cells, the late-passage HPMC exhibited increased expression of p16^INK4a but not of p21^Cip1. In addition, these cells generated more reactive oxygen species and displayed increased presence of oxidatively modified DNA (8-hydroxy-2'-deoxyguanosine). These results demonstrate that early onset of senescence in omentum-derived HPMC may be associated with oxidative stress-induced upregulation of p16^INK4a.

cellular senescence; oxidative stress

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