p53 and Myofibroblast Apoptosis in Organ Fibrosis

Abstract

Organ fibrosis represents a dysregulated, maladaptive wound repair response that results in progressive disruption of normal tissue architecture leading to detrimental deterioration in physiological function, and significant morbidity/mortality. Fibrosis is thought to contribute to nearly 50% of all deaths in the Western world with current treatment modalities effective in slowing disease progression but not effective in restoring organ function or reversing fibrotic changes. When physiological wound repair is complete, myofibroblasts are programmed to undergo cell death and self-clearance, however, in fibrosis there is a characteristic absence of myofibroblast apoptosis. It has been shown that in fibrosis, myofibroblasts adopt an apoptotic-resistant, highly proliferative phenotype leading to persistent myofibroblast activation and perpetuation of the fibrotic disease process. Recently, this pathological adaptation has been linked to dysregulated expression of tumour suppressor gene p53. In this review, we discuss p53 dysregulation and apoptotic failure in myofibroblasts and demonstrate its consistent link to fibrotic disease development in all types of organ fibrosis. An enhanced understanding of the role of p53 dysregulation and myofibroblast apoptosis may aid in future novel therapeutic and/or diagnostic strategies in organ fibrosis.

Corneal keratocytes, fibroblasts, and myofibroblasts exhibit distinct transcriptional profilesin vitro

“…The presence of myofibroblasts is important for wound closure, however, their persistence can lead to unwanted fibrosis 86,88 . In our analysis, while genes associated with proliferation were downregulated, the myofibroblasts appear to take on a similar apoptotic-resistant phenotype that is seen in pathological wound healing responses 89,90 , as indicated by changes in the cell cycle, cellular senescence, PI3K-Akt, and p53 signaling pathways. Genes within these pathways that may be of particular interest include BCL2 (upregulated in myofibroblasts compared to both keratocytes and fibroblasts), which is known to be capable of blocking apoptosis and has been a target of interest for various cancer types and in wound repair 63,91,92 .…”

The Role of Vimentin in Human Corneal Fibroblast Spreading and Myofibroblast Transformation

“…Another protein highly expressed in Vim KO and control cells is the tumor protein P53 inducible protein 3 (TP53I3), which is a potent transcription factor responsible for the induction of cell-cycle arrest, apoptosis, and senescence [60]. During pathological wound healing, myofibroblasts have been shown to adopt an apoptotic-resistant phenotype to perpetuate fibrosis [33]. Myofibroblast persistence leads to more ECM deposition, remodeling, tissue contraction, and formation of pathological scars.…”

“…Integrins such as ITGA11 are essential for strong cell-matrix attachments to resist highly contractile forces [31,32]. Tumor protein P53 inducible protein 3 (TP53I3) provides apoptotic resistance to myofibroblasts during fibrosis [33]. LMCD1 has been shown to be highly up-regulated by myofibroblasts in order to increase expression of ECM proteins and maintain high levels of αsma [34].…”

Advances in Nanoparticles in the Prevention and Treatment of Myocardial Infarction

“…In this phase, phagocytes exert a cytosolic role, and secretion occurs of anti-inflammatory cytokines by subpopulations of T-lymphocytes [ 27 ]. Meanwhile, the adult mammalian heart contains a large number of mesenchymal and perivascular fibroblasts, which transdifferentiate into myofibroblasts and secrete matrix proteins, and myofibroblasts express contractile proteins (e.g., α-smooth muscle actin), which repair the infarcted myocardium and promote the formation of scar tissue [ 28 ]. In addition, when matrix fragments in the infarcted area are phagocytosed, the organism forms a temporary matrix composed mainly of fibronectin and fibronectin, and this highly plastic matrix network serves as a scaffold for cell migration and proliferation to promote wound healing [ 26 ].…”