Long-term quiescent fibroblast cells transit into senescence.

Shiva Marthandan,Karolin Klement,Peter Hemmerich,Steffen Priebe,Stephan Diekmann,Thomas G Hofmann

doi:10.1371/journal.pone.0115597

Shiva Marthandan, Karolin Klement + Show 4 more

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https://doi.org/10.1371/journal.pone.0115597

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Abstract

Cellular senescence is described to be a consequence of telomere erosion during the replicative life span of primary human cells. Quiescence should therefore not contribute to cellular aging but rather extend lifespan. Here we tested this hypothesis and demonstrate that cultured long-term quiescent human fibroblasts transit into senescence due to similar cellular mechanisms with similar dynamics and with a similar maximum life span as proliferating controls, even under physiological oxygen conditions. Both, long-term quiescent and senescent fibroblasts almost completely fail to undergo apoptosis. The transition of long-term quiescent fibroblasts into senescence is also independent of HES1 which protects short-term quiescent cells from becoming senescent. Most significantly, DNA damage accumulates during senescence as well as during long-term quiescence at physiological oxygen levels. We suggest that telomere-independent, potentially maintenance driven gradual induction of cellular senescence during quiescence is a counterbalance to tumor development.

Highlights

Many cells within our bodies, including fibroblasts, hepatocytes, lymphocytes, stem cells and germ cells, are in the state of quiescence, defined as a reversible cell cycle arrest with temporary absence of proliferation [1]
Proliferating control MRC-5 or WI-38 fibroblasts reached maximum population doublings (PDs) of 72 or 61, respectively, whereas cells subjected to pulses of quiescence reached 69 PDs (MRC-5) or 59 PDs (WI-38)
The periods of quiescence had an influence on cellular behavior: after periods of quiescence, between same PD values MRC-5 and WI-38 fibroblast cells grew detectably slower compared to constantly proliferating control fibroblast cells (Fig. 1 A and B)

Summary

Introduction

Many cells within our bodies, including fibroblasts, hepatocytes, lymphocytes, stem cells and germ cells, are in the state of quiescence, defined as a reversible cell cycle arrest with temporary absence of proliferation [1]. Pathologies associated with quiescence include auto-immune diseases, fibrosis, and chronic wounds Some of these cells maintain a quiescent state for long periods of time, even years, and quiescent cells are defined to retain the ability to return into the cell cycle. Human diploid fibroblasts can enter quiescence in response to signals including loss of adhesion, contact inhibition, and mitogen withdrawal. Each of these anti-proliferative signals induce a major induction-specific reprogramming of gene expression, either enforcing the nondividing state by regulating genes involved in cell division, or ensuring the reversibility of quiescence by protecting cells from damage induced by free radicals, while other changes indicate the involvement in pathways protecting quiescent cells against transition into terminal differentiation [15]. Quiescence is a collection of states determined by the initiating signal; a number of genes are universally characteristic of quiescence, implying the existence of a genetic program of quiescence common to the different quiescent states [15]

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