Programmed cell senescence during embryonic development

Cellular senescence disables the proliferation of damaged cells and it is relevant for cancer and aging. Here, we show that cellular senescence occurs during mammalian embryonic development. Specifically, we have focused on the mouse regressing mesonephros and the endolymphatic sac of the inner ear. Senescence is characterized by SAbetaG activity, heterochromatinization, and proliferative arrest. Mechanistically, developmentally-programmed senescence at the mesonephros and endolymphatic sac is strictly dependent on p21, but independent of DNA damage, p53 or other cell cycle inhibitors, and it is regulated by the TGFbeta/SMAD and PI3K/FOXO pathways. Developmentally-programmed senescence is followed by macrophage infiltration and clearance of senescent cells. Abrogation of senescence by p21 deletion is only partially compensated by apoptosis and originates detectable developmental abnormalities. Importantly, high levels of p21 are also associated to the regressing mesonephros and endolymphatic sac in human embryos. These findings place cellular senescence as a relevant morphogenic process during embryonic development. We microdissected mesonephric tubules from senescent (WT) and non-senescent (p21-null) embryos to get information about this new senescence that occurs during embryogenesis.细胞衰老（cellular senescence）会使受损细胞丧失增殖能力，其与癌症及衰老过程密切相关。本研究证实，细胞衰老现象会在哺乳动物胚胎发育阶段出现。我们重点聚焦于小鼠退化中的中肾以及内耳的内淋巴囊。细胞衰老的标志性特征包括SAbetaG活性、异染色质化以及增殖停滞。从机制上来说，中肾与内淋巴囊处的发育程序性细胞衰老严格依赖p21，却不依赖DNA损伤、p53或其他细胞周期抑制剂，且该过程受TGFβ/SMAD与PI3K/FOXO通路调控。发育程序性细胞衰老会伴随巨噬细胞浸润以及衰老细胞的清除。通过敲除p21抑制细胞衰老，仅能通过细胞凋亡实现部分代偿，且会引发可检测到的发育异常。值得注意的是，人类胚胎中退化的中肾与内淋巴囊同样存在高表达的p21。上述研究结果将细胞衰老确立为胚胎发育过程中一项关键的形态发生相关过程。我们从衰老型（野生型，WT）与非衰老型（p21敲除型，p21-null）胚胎中显微切割中肾小管，以获取胚胎发生过程中这一新型衰老现象的相关信息。