背景:尽管乙酰水杨酸已被广泛用于治疗和预防各种疾病数十年,由于相互矛盾的数据,其对子宫内膜容受性和随后的妊娠率的潜在影响仍然存在争议:许多报道显示乙酰水杨酸的积极作用,而其他人发现它没有效果。此外,乙酰水杨酸对正常子宫内膜细胞各种功能的直接影响,尤其是子宫内膜干细胞,其潜在的分子机制尚未得到证实。最近,研究表明,子宫内膜组织中活性干/祖细胞数量的减少限制了子宫内膜的周期性再生,从而降低了妊娠成功率。提示子宫内膜干细胞在子宫内膜再生和随后的子宫内膜容受性中发挥关键作用。
方法:我们评估阿司匹林治疗是否可以抑制与再生能力相关的各种子宫内膜干细胞功能,比如自我更新,迁移,多能性/干性,和差异化能力,在体外。接下来,我们评估了SERPINB2是否通过靶向SERPINB2的特异性shRNA减少SERPINB2表达来调节阿司匹林对子宫内膜干细胞功能的影响.为了进一步研究阿司匹林是否也在体内抑制各种子宫内膜干细胞功能,每天通过腹膜内(i.p.)注射给予小鼠阿司匹林7天。
结果:除了先前确定的角色之外,据我们所知,我们首次发现乙酰水杨酸直接抑制与再生能力相关的各种人子宫内膜干细胞功能(即,自我更新,迁移,分化,和容量)通过其体外新的靶基因SERPINB2。乙酰水杨酸通过抑制众所周知的促生存途径发挥其功能,例如Akt和/或ERK1/2信令,通过SERPINB2信号级联。此外,我们还发现乙酰水杨酸显著抑制组织内子宫内膜干细胞的再生能力相关功能.
结论:我们发现乙酰水杨酸对与再生能力相关的各种子宫内膜干细胞功能具有不同的作用。我们的发现是朝着开发更有效的治疗策略以增加成功怀孕机会迈出的关键一步。视频摘要。
Although acetylsalicylic acid has been widely used for decades to treat and prevent various diseases, its potential effects on endometrial receptivity and subsequent pregnancy rates are still controversial due to conflicting data: many reports have shown positive effects of acetylsalicylic acid, whereas others have found that it has no effect. Furthermore, the direct effects of acetylsalicylic acid on various functions of normal endometrial cells, especially endometrial stem cells, and their underlying molecular mechanisms have not yet been proven. Recently, studies have revealed that a reduced number of active stem/progenitor cells within endometrial tissue limits cyclic endometrial regeneration and subsequently decreases pregnancy success rates, suggesting that endometrial stem cells play a critical role in endometrial regeneration and subsequent endometrial receptivity.
We assessed whether aspirin treatment can inhibit various endometrial stem cell functions related to regenerative capacity, such as self-renewal, migration, pluripotency/stemness, and differentiation capacity, in vitro. Next, we evaluated whether
SERPINB2 regulates the effects of aspirin on endometrial stem cell functions by depleting
SERPINB2 expression with specific shRNA targeting
SERPINB2. To further investigate whether aspirin also inhibits various endometrial stem cell functions in vivo, aspirin was administered daily to mice through intraperitoneal (i.p.) injection for 7 days.
In addition to its previously identified roles, to the best of our knowledge, we found for the first time that acetylsalicylic acid directly inhibits various human endometrial stem cell functions related to regenerative capacity (i.e., self-renewal, migration, differentiation, and capacity) through its novel target gene
SERPINB2 in vitro. Acetylsalicylic acid exerts its function by suppressing well-known prosurvival pathways, such as Akt and/or ERK1/2 signaling, through a
SERPINB2 signaling cascade. Moreover, we also found that acetylsalicylic acid markedly inhibits regenerative capacity-related functions in endometrial stem cells within tissue.
We have found that acetylsalicylic acid has diverse effects on various endometrial stem cell functions related to regenerative capacity. Our findings are a critical step toward the development of more effective therapeutic strategies to increase the chances of successful pregnancy. Video Abstract.