Senescent cell removal via JAG1‐NOTCH1 signalling in the epidermis

Abstract

Cellular senescence is a phenomenon characterized by irreversible cell cycle arrest. The shortening of telomeres results in cellular senescence and the replicative limit of a cell, as reported by Hayflick. 1 In addition, other reasons such as failure in regulating tumor genes or tumor suppressor genes, DNA damage caused by ionizing radiation or ultraviolet ray (UV) and oxidative stress by reactive oxygen species (ROS) production are also known to cause cellular senescence. 2 Senescent cells increase the expression of cyclin-dependent kinase inhibitors p21 (CDKN1A) and p16 (CDKN2A) and a tumor suppressor p53, and such cells stop the cell cycle. It is also known that senescent cells secrete inflammatory cytokines such as IL-1β, IL-6, a chemokine IL-8 and matrix metalloproteinases (MMPs). 3 Senescent cells reinforce senescence in an autocrine manner and also induce senescence in surrounding cells or damage them by paracrine signalling. These features are called senescence-associated secretory phenotype (SASP). [4][5][6][7] Senescent cells have been reported to increase

Hyaluronan: A key player or just a bystander in skin photoaging?

“…Based on the intensity of the stress and damage, cells may enter senescence prematurely (stress‐induced premature senescence) 80 . Senescent cells exhibit cell cycle arrest mediated by increased levels of p16, p53, and p21, an altered metabolism, macromolecular damage and a senescent‐associated secretory phenotype (SASP) 81–83 . SASP components include inflammatory mediators, growth factors and proteases 84 .…”

“…80 Senescent cells exhibit cell cycle arrest mediated by increased levels of p16, p53, and p21, an altered metabolism, macromolecular damage and a senescent-associated secretory phenotype (SASP). [81][82][83] SASP components include inflammatory mediators, growth factors and proteases. 84 However, the expression of SASP varies markedly from cell to cell.…”

Changes of senescent cell accumulation and removal in skin tissue with ageing

“…We reported that skin inherently possesses mechanisms to remove senescent cells. In the epidermis, this is achieved by the binding of JAG1, a Notch ligand expressed on adjacent non‐senescent keratinocytes, to Notch1 receptors expressed by senescent keratinocytes, which promotes the exclusion of senescent cells from the basal layer by inducing differentiation 3 . Meanwhile, in the dermis, senescent cells are phagocytosed by macrophages through recognition by the phosphatidyl serine (PS) receptor STAB1 4 .…”

“…In the epidermis, this is achieved by the binding of JAG1, a Notch ligand expressed on adjacent non-senescent keratinocytes, to Notch1 receptors expressed by senescent keratinocytes, which promotes the exclusion of senescent cells from the basal layer by inducing differentiation. 3 Meanwhile, in the dermis, senescent cells are phagocytosed by macrophages through recognition by the phosphatidyl serine (PS) receptor STAB1. 4 However, since ageing is associated with the accumulation of senescent cells in skin tissue, it is hypothesized that this accumulation is preceded by a decline in the ability to remove them.…”

Computational screen to identify potential targets for immunotherapeutic identification and removal of senescence cells

“…Using drug signatures computed from the Gene Expression Omnibus (GEO) database, the common senescence genes were significantly enriched for genes downregulated with metformin (a diabetic drug that alters cell metabolism) and genes upregulated with cisplatin (chemotherapy drug). Notably, the SenoRanger gene set was enriched for genes downregulated with overexpression of JAG1, a NOTCH1 ligand whose decrease in expression with age may reduce Notch signaling and senescent cell clearance in human skin (Yoshioka et al, 2021 ). The SenoRanger genes were also associated with a variety of transcription factors, including CBX2 (ENCODE) which was found to be an essential regulator of senescence‐associated chromosomal instability in mouse fibroblasts (Baumann et al, 2020 ).…”