Epithelial injury induces an innate repair mechanism linked to cellular senescence and fibrosis involving IGF-binding protein-5

Abstract

Fibrosis is associated with epithelial repair. It involves the activation of fibroblasts, increased production of extracellular matrix proteins and transdifferentiation to contractile, myofibroblasts that aid in wound contraction. This provisional matrix plugs the injured epithelium and provides a scaffold for epithelial cell migration, involving an epithelial-mesenchymal transition (EMT). When epithelial injury involves blood loss, this leads to platelet activation, the production of several growth factors and an acute inflammatory response. Under normal circumstances, the epithelial barrier is repaired and the inflammatory response resolves. However, in fibrotic disease, the fibroblast response continues, resulting in unresolved wound healing. The fibrotic diseases range from scleroderma, where the problem may be restricted to the skin and where it is not life-threatening, through to systemic forms that can manifest as, for example, idiopathic pulmonary fibrosis, in which death is inevitable within 3-5 years. Anti-inflammatory treatments have failed to ameliorate the disease condition and focus has instead turned to transforming growth factor-b1 (TGFB1), since it induces many of the processes involved, including fibroblast activation and EMT. Most recently, however, a new player in this process has been described, IGF-binding protein-5 (IGFBP5). IGFBP5 has also been shown to induce similar effects to TGFB1, but, in addition, it is strongly implicated in the process of senescence which is now believed to be a significant factor in these diseases. We examine the evidence for this role of IGFBP5 and identify some of the therapeutic targets which might be used to ameliorate these diseases of unknown cause.

Esophageal cancer-related gene 4 is a secreted inducer of cell senescence expressed by aged CNS precursor cells

“…However, we did not find clusters of Ecrg4+ cells in the aged brain, indicating that neighboring cells do not become senescent at one time, perhaps owing to unknown inhibitors for Ecrg4 or Ecrg4 acting in a cell-autonomous manner, as in the case of IL6 (29). Nonetheless, because other senescence-inducing secretion factors (30), including IGFBPs, IL, TGFβ, and PAI1, not only induce senescence but also cause or contribute to degenerative changes in the surrounding cells (31)(32)(33), it will be of great interest to investigate the physiological significance of Ecrg4's function. Additionally, it will be interesting to learn if its inhibition delays the processes of brain aging and if Ecrg4 contributes to differences between fetal/neonatal and adult OPCs in myelination speed and competence, as previously shown by Windrem et al (8), although Ecrg4 is unlikely to be involved in oligodendrocyte differentiation (Fig.…”

Idiopathic Pulmonary Fibrosis—an Epidemiological and Pathological Review

“…Insulin-like growth factor binding protein (IGFBP)-5 is a fairly recently identified profibrotic mediator that not only has profibrotic effects similar to those of TGFβ but also plays a role in cellular senescence [117]. This dual role makes IGFBP of particular interest in IPF in view of the increasing incidence of IPF with advancing age and the recently identified association of the disease with telomerase, another key player in cellular senescence.…”

“…This dual role makes IGFBP of particular interest in IPF in view of the increasing incidence of IPF with advancing age and the recently identified association of the disease with telomerase, another key player in cellular senescence. Overexpression of IGFBP5 in normal fibroblasts has been shown to stimulate myofibroblast differentiation and collagen synthesis in normal lung fibroblasts [117,118]. Expression of human IGFBP5 in mice resulted in cellular infiltration and collagen deposition particularly around the airways.…”

Clonal wound re‐epithelialisation after radiotherapy for skin cancer

“…6 It is common to see healthy granulation tissue at the base of skin tumours that have been successfully treated with radiotherapy (Fig. 1b).…”