背景:高龄产妇年龄与植入率和妊娠率降低有关,然而,潜在的机制仍然知之甚少,研究模式有限。
目标:这里,我们的目的是阐明衰老对着床能力的影响,利用囊胚构建一个新的研究模型。
方法:我们使用具有全能性卵裂球样细胞(TBLC)的新型三维系统来构建TBL-胚状体,并建立了源自氧化应激诱导TBLC的衰老相关胚胎模型。
结果:形态学和转录组学分析显示,TBL囊胚表现出特征性的胚泡形态,细胞谱系,和更高的发展速度的一致性。TBL-胚状体显示出在体外发育为植入后结构并成功植入小鼠子宫的能力,诱导蜕膜化和形成胚胎组织。重要的是,衰老损害了TBL囊虫的植入潜力,有效地模仿受损的植入能力和降低与高龄相关的妊娠率。此外,对人类同源蜕膜中差异表达基因(DEGs)的分析显示,多种生育相关疾病和其他妊娠并发症的富集。与这些疾病相关的基因以及在两种类型的TBL胚泡和蜕膜的谱系样细胞中鉴定出的常见DEGs可能代表了解决植入潜力受损的潜在目标。
结论:这些结果揭示了TBL囊虫是研究植入和早期植入后的改良模型,提供对高龄女性妊娠相关疾病的有价值的见解和治疗干预的潜在目标。
BACKGROUND: Advanced maternal age is associated with reduced implantation and pregnancy rates, yet the underlying mechanisms remain poorly understood, and research models are limited.
OBJECTIVE: Here, we aim to elucidate the impacts of senescence on implantation ability by employing
blastoids to construct a novel research model.
METHODS: We used a novel three-dimensional system with totipotent blastomere-like cells (TBLCs) to construct TBL-
blastoids and established senescence-related embryo models derived from oxidative stress-induced TBLCs.
RESULTS: Morphological and transcriptomic analyses revealed that TBL-blastoids exhibited characteristic blastocyst morphology, cell lineages, and a higher consistency in developmental rate. TBL-
blastoids demonstrated the ability to develop into postimplantation structures in vitro and successfully implanted into mouse uteri, inducing decidualization and forming embryonic tissues. Importantly, senescence impaired the implantation potential of TBL-
blastoids, effectively mimicking the impaired implantation ability and reduced pregnancy rates associated with advanced age. Furthermore, analysis of differentially expressed genes (DEGs) in human homologous deciduae revealed enrichment in multiple fertility-related diseases and other complications of pregnancy. The genes implicated in these diseases and the common DEGs identified in the lineage-like cells of the two types of TBL-blastoids and deciduae may represent potential targets for addressing impaired implantation potential.
CONCLUSIONS: These results unveiled that TBL
blastoids are an improved model for investigating implantation and early postimplantation, offering valuable insights into pregnancy-related disorders in women with advanced age and potential targets for therapeutic interventions.