Cellular senescence controls fibrosis in wound healing - PubMed (original) (raw)

Cellular senescence controls fibrosis in wound healing

Joon-Il Jun et al. Aging (Albany NY). 2010 Sep.

Abstract

Mammalian wound healing involves the rapid synthesis and deposition of extracellular matrix (ECM) to maintain tissue integrity during repair. This process must be tightly controlled, as its deregulation may result in fibrosis, scarring, and loss of tissue function. Recent studies have uncovered an efficient and parsimonious mechanism for rendering fibrogenesis self-limiting in wound healing: in such diverse organs as the liver and skin, the myofibroblasts that initially proliferate and produce ECM are themselves eventually driven into senescence, blocking their further proliferation and converting them into matrix-degrading cells. Myofibroblast senescence in skin wounds is triggered by a dynamically expressed matricellular protein, CCN1/CYR61, which acts through integrin-mediated induction of oxidative stress. We propose that the onset of myofibroblast senescence is a programmed wound healing response that functions as a self-limiting mechanism for fibrogenesis, and this process may be regulated by the ECM microenvironment through the expression of CCN1/CYR61.

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Conflict of interest statement

The authors of this manuscript have no conflict of interests to declare.

Figures

Figure 1.

Figure 1.. Myofibroblast senescence imposes self-limiting control on fibrogenesis during wound healing.

Upon injury, myofibroblasts derived from activated fibroblasts and from other cell types proliferate and rapidly synthesize ECM to provide tissue integrity during repair. At later stages of wound healing, these ECM-producing myofibroblasts are themselves driven into senescence, whereupon they express an ECM-degrading phenotype characteristic of senescent cells. Therefore, fibrogenesis is self-limiting as myofibroblasts undergo senescence, thereby halting the proliferation of the ECM-producing cells and promoting ECM degradation. In cutaneous wound healing, senescence is triggered by the matricellular protein CCN1.

Figure 2.

Figure 2.. A mechanistic model for CCN1-induced senescence.

The binding of CCN1 to its receptors in fibro-blasts, integrin α6β1and HSPGs, activates RAC1 and the RAC1-dependent NADPH oxidase 1 to generate a robust and sustained accumulation of ROS. This leads to a DNA damage response and activation of p53, as well as the ROS-dependent hyperactivation of ERK and p38 MAPK, leading to p16INK4a induction [22]. Both p53 and p16INK4a act upon pRb to induce senescence.

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