The Direction of Causation Between Fibrosis and Cellular Senescence
A fair amount of evidence points to senescent cells as causative of fibrosis, the deposition of scar-like collagen structures in tissue that disrupt organ function. This evidence includes reversal of fibrosis in animal models via selective destruction of senescent cells, a promising finding given the poor and limited options presently available for the treatment of fibrosis in human medicine. The paper here suggests that the relationship between fibrosis and cellular senescence is more complex, however, in that fibrotic changes in the extracellular matrix may act to induce greater levels of cellular senescence. Clearly there is more work to be done on this topic, but given the ability to destroy senescent cells via senolytic drugs, we might expect meaningful progress towards a better understanding in the years ahead.
Fibrotic diseases are characterised by deposition of excessive extracellular matrix (ECM) after injury resulting in organ dysfunction. While little is known about the exact mechanisms that result in excessive ECM deposition and accumulation in fibrotic disease, there is increasing evidence that cellular senescence is implicated in fibrosis. One major under-recognised element in fibrosis is the contribution of the ECM itself. It is known that the altered composition and increased cross-linking leads to an altered topography and stiffness. These changes alter cellular behaviour and might potentially drive cells to become senescent contributing to an environment favouring disease progression.
Increased ECM stiffness is a feature of fibrosis and is thought to result from the quantity of ECM deposition and the degree of its cross-linking. The mechanical properties of areas of wounded tissue significantly change in rat liver fibrosis. It was suggested that this was the result of increased cross-linking of the ECM fibres, rather than increased ECM deposition after the initial insult. These results suggest that cross-linking of ECM has a greater impact on stiffness and thus altered mechanical properties than the quantity of deposited ECM alone.
In fibrotic disease, the increased cross-linking has not only been associated with increased stiffness but also in higher resistance to proteolytic degradation as the conformational changes lead to less accessible epitopes for matrix metallopeptidases. The stiffness of the ECM directly influences the behaviour and function of cells including increased fibroblast proliferation, migration and contraction. Furthermore, a stiffer ECM leads to an increase in latent transforming growth factor-β (TGF-β) activation which reinforces fibrosis and it has been linked to cellular senescence. TGF-β contributes to the induction of senescence or the acceleration of transformation into senescence in various cell types.
Current therapeutic approaches for modulating senescence aim to specifically kill aberrant cells that have entered the senescent state. This includes several drugs (for example quercetin and dasatinib) that were originally developed for targeting tumours. However, as some of the markers that are present in malignant cells are also specifically expressed in senescent cells these agents have now been repurposed as senolytic agents. These drugs have been shown to effectively reduce the number of senescent cells, and in some cases decrease fibrosis, at least in preclinical models, potentially through modulation of the pro-inflammatory SASP released by the senescent cells.
In a first human, open label pilot study, the potential application of dasatinib and quercetin was tested in 14 patients with idiopathic pulmonary fibrosis. There was a significant improvement in the physical condition of the patients, but the pulmonary function of the patients did not change within this short trial period. Circulating SASP factors were measured, and while no significant change was reported there was a suggestion of reduced levels of selected proteins important for fibrotic remodelling, including IL-6, MMP, and TIMP2. Intriguingly, changes in pulmonary function and physical condition of the patients correlated with changes in the circulating levels of matrix remodelling proteins. While this is a very early study that needs to be validated in a much larger population in a randomised controlled trial, these observations further suggest that the role of the ECM should not be overlooked when striving to understand the regulation of senescence in fibrosis.