Programmed Cell Senescence during Mammalian Embryonic Development

Abstract

Cellular senescence disables proliferation in damaged cells, and it is relevant for cancer and aging. Here, we show that senescence occurs during mammalian embryonic development at multiple locations, including the mesonephros and the endolymphatic sac of the inner ear, which we have analyzed in detail. Mechanistically, senescence in both structures is strictly dependent on p21, but independent of DNA damage, p53, or other cell-cycle inhibitors, and it is regulated by the TGF-β/SMAD and PI3K/FOXO pathways. Developmentally programmed senescence is followed by macrophage infiltration, clearance of senescent cells, and tissue remodeling. Loss of senescence due to the absence of p21 is partially compensated by apoptosis but still results in detectable developmental abnormalities. Importantly, the mesonephros and endolymphatic sac of human embryos also show evidence of senescence. We conclude that the role of developmentally programmed senescence is to promote tissue remodeling and propose that this is the evolutionary origin of damage-induced senescence.

Autolysosome biogenesis and developmental senescence are regulated by both Spns1 and v-ATPase

“…Moreover, cumulative lines of evidence are consistent with the point of view that cellular senescence might evolve to optimize embryogenesis, and that its beneficial postnatal functions, to balance tumor suppression and tissue repair or regeneration, could arise and be sustained later in evolution. [1][2][3][4][5][6] We expect that our approach of analyzing evolutionary developmental mechanisms of senescence in zebrafish will accelerate the discovery of new pharmacological interventions in aging, stressmediated disorders and cancers.…”

“…[1][2][3][4][5][6] Senescence is, therefore, not only a phenomenon observed in the later aging process but is also detectable during embryogenesis of vertebrates; as such, this process might have evolved to regulate embryonic development. However, the underlying genetic and molecular basis in embryonic development and senescence remains poorly understood.…”

Senescence from G2 arrest, revisited

“…8 ), they can elicit pro-and/or anti-tumorigenic responses, depending on the microenvironment. 12 Finally, recent work has shown that senescence contributes also to tissue remodeling during embryonic development, 21,22 thus highlighting its importance in non-pathological situations. In conjunction with its role in preventing fibrosis, 23,24 these observations also raise the question as to whether fundamentally different mechanistic pathways underlie these different physiological roles of senescence.…”

Postinfarction Hearts Are Protected by Premature Senescent Cardiomyocytes Via GATA4‐Dependent CCN1 Secretion

“…Stress‐induced senescence or age‐independent premature senescence is used to describe the phenomenon in which various stressors, such as oncogenic events and ionizing radiation, instigate cellular dysfunction 6, 7. Additionally, it is becoming evident that senescence also exerts beneficial roles in normal embryonic development and tissue repair processes 8, 9, 10. Mechanically, senescent cells can affect surrounding cells and play active roles in tissue remodeling by secreting such proteins as proinflammatory cytokines, chemokines, and growth factors (senescence‐associated secretory phenotype, SASP) 11.…”