Aging Cell:高龄产妇更有可能出现胎盘早衰和畸形 

2021-06-13 haibei MedSci原创

α-Klotho的过量表达明显改善了侵袭性,但没有改变衰老生物标志物的表达。α-Klotho缺陷的小鼠表现出胎盘畸形,并导致胎盘和胎儿重量较低。

衰老被定义为随着机体年龄的增长,对机体的生存和繁殖至关重要的生理功能的恶化。据报道,许多疾病,如动脉硬化、癌症、痴呆症和慢性肾脏病,都与衰老有关。尽管衰老是环境和遗传因素相互作用的结果,但很少有基因被认为是调节衰老的关键因子,这少数基因中就包括Klotho,该基因的突变可以导致小鼠加速衰老并缩短寿命。

Klotho基因在小鼠和人类中都位于染色体13q12,编码α-Klotho蛋白。α-Klotho蛋白的缺失会导致小鼠出现多种早衰表型,包括不孕不育、动脉硬化、步态障碍、认知能力下降、皮肤萎缩和寿命缩短。而α-Klotho的过度表达可以缓解这些表型,并延长小鼠的寿命。因此,长期以来,α-Klotho被认为是一种有效的衰老抑制因子。

目前,有新的证据表明,α-Klotho在人类组织和器官中广泛表达,包括肾脏、甲状旁腺、小肠、脂肪组织和胎盘。在人类中,α-Klotho的表达水平与年龄有关,当一个人达到40岁时开始下降。

高龄产妇(AMA)妊娠与较高的围产期不良后果风险有关,这可能是由于胎盘的过早衰老造成的。目前,抗衰老蛋白α-Klotho在AMA妊娠中的表达和对胎盘的影响还没有被完全阐明。

最近,研究人员通过Western印迹和免疫组织化学(IHC)染色确定α-Klotho在小鼠和人类AMA妊娠胎盘中的表达模式,并通过操纵α-Klotho在JAR细胞中的表达,研究了其在滋养细胞衰老中的作用,并进行转孔实验以评估滋养细胞的入侵。

在小鼠和人胎盘中α-Klotho的表达模式

研究人员首先通过mRNA测序筛选出α-Klotho在JAR细胞中调控的下游基因,然后在α-Klotho基因敲除和对照JAR细胞中进行验证。研究人员还通过在GD8.5时经尾静脉注射klotho干扰腺病毒(Ad-Klotho)产生α-Klotho缺陷小鼠。结果显示,削弱α-Klotho不仅导致JAR细胞的衰老表型和侵袭性丧失,而且还导致细胞粘附分子(CAM)基因的转录减少。

α-Klotho的过量表达明显改善了侵袭性,但没有改变衰老生物标志物的表达。α-Klotho缺陷的小鼠表现出胎盘畸形,并导致胎盘和胎儿重量较低

总之,该研究结果表明,AMA导致胎盘滋养细胞中的α-Klotho表达减少,因此导致过早衰老和丧失侵袭能力(可能通过CAMs的下调),这两种情况最终导致胎盘畸形和不良围产期结局。

 

原始出处:

Zhi Chen et al. Advanced maternal age causes premature placental senescence and malformation via dysregulated α-Klotho expression in trophoblasts. Aging Cell (2021). 

 

 

 

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    2021-12-14 维他命
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    2021-06-15 wushaoling
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    2021-06-15 xlysu
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    2021-06-13 医鸣惊人

    认真学习了

    0

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