Targeting Senescent Cells in Fibrosis: Pathology, Paradox, and Practical Considerations

Abstract

Multi-action and temporal considerations influence deleterious versus beneficial actions of senescent cells. Acutely generated senescent cells can limit proliferation, and the senescence-associated secretory phenotype (SASP) contains factors that can facilitate tissue repair. Long-lived senescent cells that evade clearance or are generated outside of programmed remodeling can deplete the progenitor pool to exhaust regenerative capacity and through the SASP, stimulate continual activation, leading to disorganized tissue architecture, fibrotic damage, sterile inflammation, and induction of bystander senescence. Senescent cells contribute to fibrotic pathogenesis in multiple tissues, including the liver, kidney, and lung. Senotherapeutics may be a viable strategy for treatment of a range of fibrotic conditions.

Insulin-Like Growth Factor Binding Protein-5 in Physiology and Disease

“…IGFBP-5 has been found to be altered in various disease states (120)(121)(122)(123), providing the possibility of using this protein as a marker of disease progression, and hinting that altered IGFBP-5 expression may have pathophysiological relevance. Altered levels of IGFBP-5 have been detected in many types of cancer.…”

“…The accumulation of senescent cells in the arteries of children with the premature aging disease Hutchinson-Gilford Progeria seems to be the cause of their severe accelerated atherosclerosis and premature death from resulting stroke or heart attack before age 20 (152,153). Senescent cells exhibit a senescence-associated secretory phenotype that is characterized by excessive production of ECM components, and this may play a role in tissue fibrosis (122). IGFBP-5 was upregulated in senescent human umbilical vein endothelial cells and knock down of IGFBP-5 partially reversed the senescence, suggesting a role for IGFBP-5 in promoting cellular senescence (145).…”

Fibronectin in Cancer: Friend or Foe

“…However, when endothelia are situated within tumor tissues where tumor cells release factors to trigger angiogenesis with altered junctional compositions [154,155], hyperpermeability of tumor vessels renders pro-tumor leukocyte recruitment and persistent influx of plasma molecules, e.g., FN and fibrin, into chronic inflammatory TMEs, consequently facilitating tumor growth, migration/invasion, and intravasation [149,153,[156][157][158]. Fibroblasts surrounding tumor cells are generally considered as the main professional matrix producers called CAFs [145,159,160]. In the beginning of oncogenic processes, pro-inflammatory cytokines in non-autonomous SASP [113,161], produced and secreted by the senescent parenchymal cells that suffer diversity of stresses, are essentially responsible for the alteration of surrounding microenvironments, including fibroblast activities [162,163].…”

Surviving Acute Organ Failure: Cell Polyploidization and Progenitor Proliferation

“…Indeed, cell cycle arrest upon polyploidization and cellular hyperfunction represents a hypersecretory state that is also associated with a persistent secretion of profibrotic mediators driving fibrogenesis, that is, cell senescence [87]. The association of tissue polyploidization, fibrosis, and senescence, has been demonstrated for the liver [88,89], heart [89,90], and is likely to account also for kidney fibrosis [91]. In all of these organs, polyploidization may also lead to fibrosis and organ dysfunction through another mechanism.…”