Anisha Lobo

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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