The senescence-associated secretory phenotype induces cellular plasticity and tissue regeneration

Abstract

Senescence is a form of cell cycle arrest induced by stress such as DNA damage and oncogenes. However, while arrested, senescent cells secrete a variety of proteins collectively known as the senescence-associated secretory phenotype (SASP), which can reinforce the arrest and induce senescence in a paracrine manner. However, the SASP has also been shown to favor embryonic development, wound healing, and even tumor growth, suggesting more complex physiological roles than currently understood. Here we uncover timely new functions of the SASP in promoting a proregenerative response through the induction of cell plasticity and stemness. We show that primary mouse keratinocytes transiently exposed to the SASP exhibit increased expression of stem cell markers and regenerative capacity in vivo. However, prolonged exposure to the SASP causes a subsequent cell-intrinsic senescence arrest to counter the continued regenerative stimuli. Finally, by inducing senescence in single cells in vivo in the liver, we demonstrate that this activates tissue-specific expression of stem cell markers. Together, this work uncovers a primary and beneficial role for the SASP in promoting cell plasticity and tissue regeneration and introduces the concept that transient therapeutic delivery of senescent cells could be harnessed to drive tissue regeneration.

Putting p53 in Context

“…During an initial proliferative phase of regeneration, mitogens are activated and p53 must be suppressed to allow tissue remodeling (Charni et al., 2017). By triggering cellular senescence, p53 promotes the release of secretory factors that allow resolution of fibrosis (Krizhanovsky et al, 2008) and coordinate ECM remodeling (Ritschka et al, 2017). Of note, the requirement for p53 to regulate plasticity appears to be evolutionarily conserved, which requires the coordinate suppression and derepression of p53 during salamander limb regeneration (Yun et al, 2013).…”

“…For example, the p53-driven senescence associated secretory phenotype (SASP) in tumor stroma can create a tumor suppressive immune milieu that influences the incidence of cancer (Lujambio et al., 2013; Xue et al, 2007). In other settings, the SASP can be tumor promoting, by inducing epithelial–mesenchymal transition (EMT) (Laberge et al, 2012; Ritschka et al, 2017). …”

Senescent cells: an emerging target for diseases of ageing

“…MMP activity and hepatocyte growth factor have indirect and direct effects on tumour proliferation, respectively 74 . Intriguingly, the SASP has been shown to induce stem cell features in a paracrine manner 71 , which may explain the observations of SNC-driven carcinogenesis and tissue repair. In other cases, SNCs — presumably through the SASP — have been shown to drive age-related diseases or disorders 8,10,11 , but a link between a specific SASP factor (or factors) and these phenotypes is more speculative.…”

“…Thus, the SASP can be both tumour-suppressive and tumour-promoting, possibly because an acute, time- limited SASP that effectively engages immune surveillance of SNCs may be beneficial, whereas a chronic, protracted SASP may not (BOX 1). Similarly, brief exposure to SNCs promotes keratinocyte- regenerative capacity in a skin transplantation model in vivo , but prolonged contact inhibits repopulation capacity 71 . This could indicate that, under conditions of injury requiring repair, SNCs produce a SASP that initially activates resident stem cells but is inherently self-limiting.…”

Escape from senescence boosts tumour growth

“…This is not the first indication that senescence might come at a cost. For example, senescent cells secrete a range of cytokine proteins that have a tumour-promoting effect on cancer cells in the vicinity by stimulating the stem-cell properties of such cells 7,8 . Milanovic and colleagues' work, however, goes beyond observations of an indirect effect by revealing that senescent tumours have an intrinsic capacity to form an increased proportion of cancer stem cells.…”