Research Laboratories, Nippon Menard Cosmetic Co., Ltd., Nagoya, Japan.
Department of Applied Cell and Regenerative Medicine, Fujita Health University School of Medicine, Toyoake, Japan.
Exp Dermatol. 2021 Sep;30(9):1268-1278. doi: 10.1111/exd.14361. Epub 2021 May 3.
Emerging evidence has pointed to the noxious effects of senescent cells in various tissues, and senescent cells in the epidermis are known to accumulate with age. We hypothesized that there is a mechanism by which senescent cells in the epidermis are preferentially removed and that the function of such removal mechanism declines as age increases. In this study, we investigated whether Notch signalling is involved in such senescent cell removal. We found that Notch1 receptor was expressed more highly in p16INK4a-positive senescent cells than in surrounding cells in human epidermis both in young and old subjects. On the other hand, the expression of its ligand JAG1 was decreased in the epidermis of aged subjects. When normal epidermal cells and UVB-irradiated senescent cells were mixed and three-dimensional reconstructed epidermis was developed in vitro, the senescent cells were preferentially removed from the basal layer and located in the upper layer. We also found that the depletion of senescent cells from the basal layer was suppressed by JAG1 knockdown in normal cells or using a Notch signalling inhibitor. From these results, Notch signalling may be involved in senescent cell removal in the epidermis and the age-related decrease of JAG1 expression in the basal layer may lead to accumulation of senescent cells owing to reduced activation of Notch signalling.
新出现的证据表明衰老细胞在各种组织中具有有害作用，已知表皮中的衰老细胞随着年龄的增长而积累。我们假设存在一种机制，可以优先去除表皮中的衰老细胞，并且随着年龄的增长，这种去除机制的功能会下降。在这项研究中，我们研究了 Notch 信号是否参与这种衰老细胞的清除。我们发现 Notch1 受体在年轻和老年受试者的人表皮中 p16INK4a 阳性衰老细胞中的表达高于周围细胞。另一方面，其配体 JAG1 的表达在老年受试者的表皮中降低。当正常表皮细胞和 UVB 照射的衰老细胞混合并在体外进行三维重建表皮时，衰老细胞优先从基底层去除并位于上层。我们还发现，正常细胞中 JAG1 的敲低或使用 Notch 信号抑制剂抑制了基底层中衰老细胞的耗竭。从这些结果来看，Notch 信号可能参与表皮中衰老细胞的清除，而基底细胞中 JAG1 表达的年龄相关性下降可能导致由于 Notch 信号激活减少而导致衰老细胞的积累。
