Mathon, Nicole Frances; (2003) Replicative lifespan in rodent cells. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Replicative limits have been thought to constrain the extended proliferation of primary cells. After dividing a set number of times, cells irreversibly withdraw from the cell cycle and adopt a characteristic phenotype in a process defined as cellular senescence. The certainty that all cells will ultimately senescence has resulted in a finite replicative capacity being used as one of the defining features of primary cells. In this thesis I show that primary rat Schwann cells can proliferate indefinitely in culture without acquiring immortalizing mutations. These results demonstrate that senescence can no longer be considered an unavoidable barrier to primary cell culture. The only known mechanism of limiting replicative lifespan is telomere shortening, which occurs upon division of telomerase negative cells. Other uncharacterised cell-intrinsic mechanisms were thought to regulate lifespan in cells that normally express telomerase yet senesce in culture. I show that senescence can be induced in primary Schwann cells, which express telomerase, by altering the conditions in which they are cultured. These results provide the first demonstration that extrinsic as well as intrinsic factors can regulate replicative lifespan and has fuelled speculation that senescence in telomerase positive cells may also be induced by external conditions rather than an intrinsic cell division timer. The cyclin-dependent kinase inhibitor p16INK4A progressively upregulated in most primary cell types as they divide in culture. This induction was thought to be a response to an intrinsic timer that operated to limit replicative capacity. I demonstrate that p16INKA induction in rat Schwann cells can be uncoupled from a senescent arrest. Moreover, the rate and level of p16INKA induction is dependent on the conditions in which the cells are cultured. These results demonstrate that p16INKA4A induction in primary Schwann cells is a response to extrinsic signals rather than an intrinsic cell division timer.

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