Abstract
BackgroundTerminally differentiated (TD) cells permanently exit the mitotic cycle while acquiring specialized characteristics. Although TD cells can be forced to reenter the cell cycle by different means, they cannot be made to stably proliferate, as attempts to induce their replication constantly result in cell death or indefinite growth arrest. There is currently no biological explanation for this failure.Principal FindingsHere we show that TD mouse myotubes, reactivated by depletion of the p21 and p27 cell cycle inhibitors, are unable to complete DNA replication and sustain heavy DNA damage, which triggers apoptosis or results in mitotic catastrophe. In striking contrast, quiescent, non-TD fibroblasts and myoblasts, reactivated in the same way, fully replicate their DNA, do not suffer DNA damage, and proliferate even in the absence of growth factors. Similar results are obtained when myotubes and fibroblasts are reactivated by forced expression of E1A or cyclin D1 and cdk4.ConclusionsWe conclude that the inability of myotubes to complete DNA replication must be ascribed to peculiar features inherent in their TD state, rather than to the reactivation method. On reviewing the literature concerning reactivation of other TD cell types, we propose that similar mechanisms underlie the general inability of all kinds of TD cells to proliferate in response to otherwise mitogenic stimuli. These results define an unexpected basis for the well known incompetence of mammalian postmitotic cells to proliferate. Furthermore, this trait might contribute to explain the inability of these cells to play a role in tissue repair, unlike their counterparts in extensively regenerating species.
Highlights
Our persistent inability to induce proliferation of terminally differentiated (TD) cells has no definite biological basis
We conclude that the inability of myotubes to complete DNA replication must be ascribed to peculiar features inherent in their Terminally differentiated (TD) state, rather than to the reactivation method
On reviewing the literature concerning reactivation of other TD cell types, we propose that similar mechanisms underlie the general inability of all kinds of TD cells to proliferate in response to otherwise mitogenic stimuli
Summary
Our persistent inability to induce proliferation of terminally differentiated (TD) cells has no definite biological basis. Terminal differentiation is defined by the permanent exit from the cell cycle that takes place in the course of acquiring functional specialization. TD cells, once thought to be utterly incapable of reentering the cell cycle, have been shown to possess a largely functional proliferation machinery that can be reactivated by a number of experimental manipulations. Various types of TD cells have been reactivated by exploiting oncogenic viruses such as polyomavirus [3], SV40 [4,5,6], adenovirus [7], or papillomavirus [8]. Differentiated (TD) cells permanently exit the mitotic cycle while acquiring specialized characteristics.
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