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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. [ABSTRACT FROM AUTHOR]

Cellular senescence is an irreversible form of cell cycle arrest that has been linked to several pathological conditions. In particular, senescence can function as a tumor suppressor mechanism, but is also thought to contribute to organismal aging. Paradoxically however, through the secretion of various factors, collectively termed the senescence-associated secretory phenotype (SASP), senescent cells can also have tumor-promoting and tissue-remodeling functions. In addition, senescent cells can play beneficial roles in tissue repair and wound healing, and reconciling these contradictory features from an evolutionary standpoint has been challenging. Moreover, senescent cells had not previously been documented in non-pathological conditions. Recently however, 2 studies have identified cellular senescence as a programmed mechanism that contributes to tissue patterning and remodeling during normal embryonic development. These findings have significant implications for our understanding of cellular senescence and help to clarify the paradoxes and the evolutionary origin of this process. [ABSTRACT FROM PUBLISHER]

Summary: Senescence is a form of cell-cycle arrest linked to tumor suppression and aging. However, it remains controversial and has not been documented in nonpathologic states. Here we describe senescence as a normal developmental mechanism found throughout the embryo, including the apical ectodermal ridge (AER) and the neural roof plate, two signaling centers in embryonic patterning. Embryonic senescent cells are nonproliferative and share features with oncogene-induced senescence (OIS), including expression of p21, p15, and mediators of the senescence-associated secretory phenotype (SASP). Interestingly, mice deficient in p21 have defects in embryonic senescence, AER maintenance, and patterning. Surprisingly, the underlying mesenchyme was identified as a source for senescence instruction in the AER, whereas the ultimate fate of these senescent cells is apoptosis and macrophage-mediated clearance. We propose that senescence is a normal programmed mechanism that plays instructive roles in development, and that OIS is an evolutionarily adapted reactivation of a developmental process. [Copyright &y& Elsevier]