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
Cellular senescence is a state comprising an essentially irreversible proliferative arrest combined with phenotypic changes and pronounced secretory activity. Although senescence has long been linked with aging, recent studies have uncovered functional roles for senescence in embryonic development, regeneration and reprogramming, and have helped to advance our understanding of this process as a highly coordinated and programmed cellular state. In this Primer article, we summarize some of the key findings in the field and attempt to explain them in a simple model that reconciles the normal and pathological roles for senescence. We discuss how a primary role of cellular senescence is to contribute to normal development, cell plasticity and tissue repair, as a dynamic and tightly regulated cellular program. However, when this process is perturbed, the beneficial effects turn detrimental and can contribute to disease and aging.