Cellular senescence controls fibrosis in wound healing

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.

Mechanisms of Lung Fibrosis Resolution

“…81 Similarly, in a mouse model of skin wounding, recruited myofibroblasts are driven into senescence at later stages of wound healing, whereupon they stopped proliferating and up-regulated expression of MMPs while also down-regulating expression of collagen and TGFb. 82 This myofibroblast senescence is triggered by the matricellular protein CCN1, which directly binds to integrin a 6 b 1 activating RAC1 to trigger accumulation of reactive oxygen species and damage response pathways inducing senescence. 83 In mice expressing a mutant CCN1 protein that is defective in integrin binding and hence in inducing senescence, the wounds were deficient in senescent cells and mice healed with significantly more fibrosis.…”

“…83 In mice expressing a mutant CCN1 protein that is defective in integrin binding and hence in inducing senescence, the wounds were deficient in senescent cells and mice healed with significantly more fibrosis. 82 The role of senescence pathways in lung myofibroblasts is less understood. A transient senescence response was observed in fibroblasts from young mice with resolving bleomycin-induced fibrosis supporting a role for senescence in spontaneous lung fibrosis resolution.…”

Integrins in Wound Healing

“…146,148 Members of the CCN family of matricellular proteins are ligands for many integrins (Table 2), 60 and they critically regulate myofibroblast fate as well as ECM production and remodeling in wounds. 142 In chronic human wounds, the expression of CCN1/Cyr61 is increased, and CCN2/CTGF is significantly reduced compared with normally healing wounds. 149 The excessive expression of CCN1/ Cyr61 may result in premature a 6 b 1 -integrinmediated myofibroblast senescence that is associated with early down-regulation of ECM (e.g., collagen) production, up-regulation of matrix-degrading proteases, and ongoing breakdown of the granulation tissue before the re-epithelialization is completed, contributing to the wound chronicity.…”

“…141,142 This process is mediated by collaborative interaction of a 6 b 1 integrin and cell surface heparan sulphate proteoglycans with matricellular protein CCN1/Cyr61 and by subsequent production of ROS. 142 Myofibroblasts persist in fibrotic conditions and pathological scars, where they continue to produce matrix.…”

“…141,142 This process is mediated by collaborative interaction of a 6 b 1 integrin and cell surface heparan sulphate proteoglycans with matricellular protein CCN1/Cyr61 and by subsequent production of ROS. 142 Myofibroblasts persist in fibrotic conditions and pathological scars, where they continue to produce matrix. 141 However, the number of myofibroblasts in the oral mucosal wounds, which heal with minimal scarring, is higher than in skin wounds, 143 suggesting that the presence of myofibroblasts per se does not predict scarring or fibrosis.…”