Physiological impact of cell senescence in vivo: Limiting Tissue Damage

In addition to their tumor suppression function, senescent cells also play a beneficial role in non-cancer pathology by limiting tissue fibrosis.   For instance, tissue damage within the liver stimulates the activation of hepatic stellate cells (HSCs), which hyper- proliferate and secrete extracellular matrix components to form a fibrotic scar.  Hyper- proliferation of HSCs induces cell senescence leading to a reduction in the secretion of ECM proteins and enhanced secretion of ECM degrading proteins, thereby limiting fibrosis.  Senescent HSCs are then eliminated in a timely manner by immune cells such as natural killer (NK) cells.  When the mechanisms leading to NK cell mediated elimination are disabled, fibrosis is increased.  In mice lacking molecular components required for induction of cell senescence, HSCs continue to proliferate, depositing ECM components and elevating the fibrotic response.  Therefore, induction of senescence in HSCs prevents short-term tissue damage by limiting fibrosis.  In addition to the liver, a similar process occurs during tissue repair within the pancreas by senescent pancreatic stellate cells.   In this instance, it was suggested that lymphocytes at the sites of wounds might play a duel-specific role in pancreatic fibrogenesis by triggering both the initiation of wound healing by activating stellate cells and its completion by clearance of senescent stellate cells.

Cell senescence also limits tissue damage at sites of cutaneous wound healing, where secretion of CCN1 induces fibroblast senescence associated with an elevation in the DNA damage response and the activation of p53 and RAC1-NOX1 complex.  The expression of anti-fibrotic genes by CCN1-induced senescent cells prevented excess fibrosis, whereas mice that express a senescence-defective Ccn1 mutant resulted in elevated fibrosis.    CCN1 also appears to play a role in the regression of liver fibrosis through induction of cell senescence in HSCs.  Therefore, cell senescence is a mechanism that limits tissue damage in multiple tissues and serves not only to restrain the damage, but also to initiate the repair and return the tissue to the pre-damaged state.

Link: Dominick G. A. Burton, Valery Krizhanovsky. Physiological and pathological consequences of cellular senescence. CMLS (2014) 

Physiological impact of cell senescence in vivo: Tumour suppression

While the history of research on cell senescence counts for more than half a century, only in the last 10 years the functional relevance of cell senescence in vivo was established. The irreversible cell cycle arrest in OIS cells makes it an ideal mechanism to prevent tumour formation following oncogene activation, and in the first functional in vivo studies, cell senescence was established as a tumour suppressor mechanism.  OIS has been shown to be important for preventing lymphoma development and contribute to response to therapy. Using transgenic mice models to bypass the senescence response to oncogenic N-Ras resulted in the development of invasive T-cell lymphomas, whereas control mice only develop non-lymphoid neoplasia at a much later time point.     Another mouse model using inducible K-ras was used to make pre-malignant lesions that can develop into malignant tumours in lung and pancreas.  In these models,  biomarkers  of  cell  senescence  were  predominantly  identified  in  the  pre- malignant lesions but were lost once tumours developed.  To investigate OIS in vivo, a number of studies have focused on human nevi (moles), which are benign tumours of melanocytes that frequently harbor oncogenic mutations of BRAF.  The congenital nevi stained positive for markers of OIS, but not DNA damage in this instance.  BrafE600V, which is present in the nevi, induced p16(INK4a) expression in growth-arrested melanocytes both in vitro and in situ.  In contrast, another study in premalignant melanocytic lesions did show the presence of DNA damage foci, primarily located at telomeric regions as well as the p16(INK4a) expression.  In addition to activating mutations in oncogenes, cell senescence can be induced as a result of loss of tumor suppressor Pten in the prostate. Therefore, these combined studies clearly demonstrate that cell senescence acts as a potent tumor suppressor mechanism that prevents the development of multiple malignancies.

Link: Dominick G. A. Burton, Valery Krizhanovsky. Physiological and pathological consequences of cellular senescence. CMLS (2014) 

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Why induce Cellular Senescence Rather than Apoptosis?

When cells become senescent in vitro they often become resistant to apoptotic stimuli in comparison to proliferating cells.  It can be speculated that if immune cells are necessary for eliminating senescent cells, the pro-survival phenotype of senescent cells may function to favor such elimination. In conjunction with regulating immune ligands and the secretory phenotype, persistent activation of the DDR, particularly double strand breaks (DSBs), may also promote a pro-survival response to facilitate DNA repair. However, if senescent cells are not removed by the immune system, this pro-survival phenotype inadvertently promotes their persistence in tissues.  Alternatively, the pro- survival phenotype of senescent cells may be an adaptive response mediated by stresses within the microenvironment to facilitate protection from further stress.

The question still arises as to why senescent cells may favor removal by the immune system rather than undergoing programmed cell death.  One plausible explanation could be related to the potential function of senescent cells during cellular repair following tissue damage.  During wound healing, senescent cells most likely play a positive role by (1) secreting chemo-attractants that recruit and activate immune cells to the site of injury, (2) secrete growth factors to stimulate cellular proliferation required for cellular replacement and protein synthesis and (3) the secretion of proteases to debride damaged tissue.  In addition, senescent cells may help to preserve tissue integrity during wound healing, that may otherwise be lost if cells underwent apoptosis, until such time that non- resident cells from other sources, such as stem cells are present to repopulate the tissue with functional cells.  In an orchestrated response, senescent cells would be subsequently eliminated by the immune system when no longer required.

Link: Physiological and Pathological Consequences of Cellular Senescence

Promiscuous Gene Expression in Senescent Cells

The main molecular pathways of senescence, persistent DDR and Rb lead to sustained chromatin remodeling within senescent cells. This stochastic remodeling of chromatin in senescent cells most likely facilitates promiscuous gene expression associated with cell senescence. Promiscuous gene expression refers to changes in gene expression not normally associated with non- senescent counterparts of the same cell type.  Promiscuous gene expression is often observed in microarray data and other analysis of gene expression of senescent verses their non- senescent counterparts and appears to also be cell-type specific. It is hypothesised that chromatin rearrangement would allow access to DNA normally tightly packed and restrict other areas of chromatin that are normally open. It has also been suggested that DNA damage may modulate gene expression by altering the binding capacity of transcription factors. In addition, changes in DNA methylation associated with cell senescence may also contribute to promiscuous gene expression. Therefore, genes that may normally be expressed can be suppressed and genes normally suppressed become expressed.

Cellular Dysfunction

A negative consequence of promiscuous gene expression in senescent cells is impairment in cellular function, the inability of cells to carry out their designated normal processes. As a result, the accumulation of these dysfunctional cells most likely leads to tissue dysfunction which compromises tissue structure and function, promoting disease. For example, a study using Klotho-deficient mice, which exhibit an accelerated ageing-like phenotype, investigated whether preventing cell senescence improves health-span in these mice. Plasminogen activator inhibitor-1 (PAI-1) is elevated in Klotho- deficient mice and is a known regulator of cell senescence. Klotho-deficient mice deficient in PAI-1 was reported to delay the induction of cell senescence, extending median lifespan and preserving organ structure and function. Another example of senescent cells that can no longer undertake their normal function might include senescent pancreatic beta cells that have impaired insulin release during diabetes and senescent vascular endothelial cells that display decreased activity of nitric oxide synthase (NOS). NOS is important for the production of nitric oxide (NO) required for maintaining vascular homeostasis and a decrease in NO production is associated with increased risk of cardiovascular disease. Therefore, a better understanding of the differences in the phenotype of senescent cells of different cell-types in relation to their in vivo function, is required to better understand mechanisms of disease development.

Links:

PAI-1–regulated extracellular proteolysis governs senescence and survival in Klotho mice

Physiological and pathological consequences of cellular senescence