Successful pregnancy is supported by a healthy maternal–fetal interface (i.e., the decidual tissues) which holds the conceptus and safeguards it against stressors from the beginning of pregnancy. Any disturbance of this interface can presumably lead to the loss of pregnancy. The use of the immunosuppressive drug mycophenolic acid (MPA) should be discontinued in pregnancy given its abortive and embryotoxic effects. Direct teratogenic effects have been observed in mammalian embryos cultured in MPA, but the underlying mechanisms of abortion by MPA are less understood. Decidual stromal cells isolated from human placentas are cultured in the presence of clinically relevant doses of MPA. Data regarding the effects of MPA on the proliferation and viability of decidua cultures are first analysed and then, molecular pathways contributing to these effects are unravelled. MPA treatment of decidual stromal cells results in loss of proliferation capacity and a decrease in the viability of decidua cultures. The molecular pathways involved in the effects of MPA on decidual stromal cells are a reduction in pre-rRNA synthesis and subsequent disruption of the nucleolus. The nucleolar stress stabilizes p53, which in turn, leads to a p21–mediated cell cycle arrest in late S and G2 phases, preventing the progression of the decidua cells into the mitosis. Furthermore, MPA does not induce apoptosis but activate mechanisms of autophagy and senescence in decidual stromal cells. The irreversible growth arrest of decidua cells, whose role in the maintenance of the pregnancy microenvironment is known, may be one cause of miscarriage in MPA treated pregnant women.

中文翻译：

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胎盘蜕膜细胞过早衰老可能是霉酚酸产生的流产原因

健康的母胎界面（即蜕膜组织）支持成功的怀孕，该界面从怀孕开始就可以保持受孕并保护其免受压力因素的影响。该界面的任何干扰都可能导致流产。鉴于其流产和胚胎毒性作用，应在怀孕期间停止使用免疫抑制药物霉酚酸 (MPA)。在 MPA 中培养的哺乳动物胚胎中已观察到直接致畸作用，但 MPA 导致流产的潜在机制尚不清楚。从人胎盘分离的蜕膜基质细胞在临床相关剂量的 MPA 存在下进行培养。首先分析关于 MPA 对蜕膜培养物增殖和活力影响的数据，然后，导致这些影响的分子途径被解开。蜕膜基质细胞的 MPA 处理导致增殖能力的丧失和蜕膜培养物的活力降低。MPA 对蜕膜基质细胞的影响所涉及的分子途径是减少前体 rRNA 合成和随后的核仁破坏。核仁应激稳定 p53，进而导致 p21 介导的细胞周期在 S 期和 G2 后期停滞，阻止蜕膜细胞进入有丝分裂。此外，MPA 不会诱导细胞凋亡，但会激活蜕膜基质细胞的自噬和衰老机制。蜕膜细胞的不可逆生长停滞（其在维持妊娠微环境中的作用是已知的）可能是 MPA 治疗的孕妇流产的原因之一。