The Role of p53 Target p21 and Nuclear Factor-κb Modulating Cellular Senescence in Hepatic Fibrosis
Introduction: Liver fibrosis is a heightened production of scar tissue due to chronic stress or injury to hepatocytes.1 Hepatic fibrosis is a result of chronic damage to hepatocytes that results in increased levels of extracellular matrix production.2 Due to the chronic impact of stress to hepatocytes, senescent cells have been found in aging cells and in liver fibrosis.3 Senescence is a process of cell cycle arrest intended to prevent the progression of pre-malignant cells.4 The p53 target p21, a cyclin-dependent kinase inhibitor, prevents the phosphorylation of retinoblastoma protein which leads to halting of proliferation, which induces senescence.5 Acutely, senescent cells aim to prevent the development of cancer, but the chronic accumulation of senescent cells can lead to pathologenesis.3 Senescent cells are resistant to apoptosis.5 Senescent cells that accumulate during aging lead to a proinflammatory state resulting in pathogenesis.6 Methods: One study investigated Senescence Associated Secretory Phenotype (SASP) through qPCR and gene expression arrays of hepatocytes to characterize the role and composition of SASPs.3 To determine the role of p21 in cellular senescence, an in-vivo mouse model was developed.5 Fibrosis was induced through the injection of CCl4.5 After the mice were killed, their livers were stained for senescence-associated beta-gal (SA-b-gal), a senescent cell marker.5 Results: The SASP of senescent hepatocytes was confirmed through cytochemical staining of p21 and senescence-associated- β-galactosidase.3 It was found that the hepatocyte SASP included chemokine production including IL-6, IL-32, and IL-8.3 p21 knock out mice exhibited an absence of senescent hepatic stellate cells, fibrosis, and collagen production.5 p21 knockout mice also exhibited less production of ECM compared to the Wild Type (WT).5 The WT mice exhibited an accumulation of senescent cells, particularly in fibrotic regions. The TGF-b signaling pathway was genetically modified in p21 knock out mice.5 The TGF-b pathway is responsible for the activation of fibroblasts and thus production of excess extracellular matrix (ECM).5 Conclusion: Senescent cells are able to accumulate due to their resistance to apoptosis through the upregulation of anti-apoptotic factors like BCl-xL and EFNB1.6 These mechanisms have been associated with increased levels of p21 and SA-b-gal, senescent cell markers.6 Researchers developed senolytic drug therapies, Dasatanib and Quercetin to target these mechanisms, thereby inducing apoptosis of senescent cells and reducing fibrosis.6
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- Yosef R, Pilpel N, Papismadov N, et al. p21 maintains senescent cell viability under persistent DNA damage response by restraining JNK and caspase signaling. The EMBO Journal. 2017;36(15):2280-2295.
- Zhifeng Gu, Jinxia Jiang, Wei Tan, et al. p53/p21 pathway involved in mediating cellular senescence of bone marrow-derived mesenchymal stem cells from systemic lupus erythematosus patients. Clinical & Developmental Immunology. 2013;2013:134243-13.
- Zhu Y, Tchkonia T, Pirtskhalava T, et al. The achilles’ heel of senescent cells: From transcriptome to senolytic drugs. Aging Cell. 2015;14(4):644-658.