RESUMO
Young mammals possess a limited regenerative capacity in some tissues, which is lost upon maturation. We investigated whether cellular senescence might play a role in such loss during liver regeneration. We found that following partial hepatectomy, the senescence-associated genes p21, p16Ink4a, and p19Arf become dynamically expressed in different cell types when regenerative capacity decreases, but without a full senescent response. However, we show that treatment with a senescence-inhibiting drug improves regeneration, by disrupting aberrantly prolonged p21 expression. This work suggests that senescence may initially develop from heterogeneous cellular responses, and that senotherapeutic drugs might be useful in promoting organ regeneration.
Assuntos
Compostos de Bifenilo/farmacologia , Inibidor de Quinase Dependente de Ciclina p21/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Fígado/fisiologia , Nitrofenóis/farmacologia , Regeneração/efeitos dos fármacos , Sulfonamidas/farmacologia , Animais , Células Cultivadas , Senescência Celular/efeitos dos fármacos , Inibidor p16 de Quinase Dependente de Ciclina/genética , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Modelos Animais , Piperazinas/farmacologiaRESUMO
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.
Assuntos
Plasticidade Celular/fisiologia , Senescência Celular/fisiologia , Regeneração/fisiologia , Via Secretória/fisiologia , Animais , Biomarcadores/metabolismo , Plasticidade Celular/genética , Células Cultivadas , Senescência Celular/genética , Células Epiteliais/citologia , Células Epiteliais/fisiologia , Feminino , Deleção de Genes , Regulação da Expressão Gênica no Desenvolvimento/genética , Queratinócitos/citologia , Queratinócitos/fisiologia , Fígado/citologia , Fígado/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/genética , Fenótipo , Regeneração/genética , Via Secretória/genética , Células-Tronco/metabolismoRESUMO
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.
