Kannan Athilakshmi, Beal Jacob R, Neff Alison M, Bagchi Milan K, Bagchi Indrani C
Department of Comparative Biosciences, University of Illinois Urbana-Champaign, 2001 S Lincoln, Urbana, IL 61802, USA.
Department of Molecular and Integrative Physiology, University of Illinois Urbana-Champaign, 407 S Goodwin, Urbana, IL 61801, USA.
PNAS Nexus. 2023 Jun 30;2(7):pgad215. doi: 10.1093/pnasnexus/pgad215. eCollection 2023 Jul.
During early pregnancy in humans and rodents, uterine stromal cells undergo a remarkable differentiation to form the decidua, a transient maternal tissue that supports the growing fetus. It is important to understand the key decidual pathways that orchestrate the proper development of the placenta, a key structure at the maternal-fetal interface. We discovered that ablation of expression of the transcription factor Runx1 in decidual stromal cells in a conditional -null mouse model () causes fetal lethality during placentation. Further phenotypic analysis revealed that uteri of pregnant mice exhibited severely compromised decidual angiogenesis and a lack of trophoblast differentiation and migration, resulting in impaired spiral artery remodeling. Gene expression profiling using uteri from and control mice revealed that Runx1 directly controls the decidual expression of the gap junction protein connexin 43 (also known as GJA1), which was previously shown to be essential for decidual angiogenesis. Our study also revealed that Runx1 controls the expression of insulin-like growth factor (IGF) 2 and IGF-binding protein 4 (IGFBP4) during early pregnancy. While Runx1 deficiency drastically reduced the production of IGF2 by the decidual cells, we observed concurrent elevated expression of the IGFBP4, which regulates the bioavailability of IGFs, thereby controlling trophoblast differentiation. We posit that dysregulated expression of GJA1, IGF2, and IGFBP4 in decidua contributes to the observed defects in uterine angiogenesis, trophoblast differentiation, and vascular remodeling. This study therefore provides unique insights into key maternal pathways that control the early phases of maternal-fetal interactions within a critical window during placental development.
在人类和啮齿动物的妊娠早期，子宫基质细胞会发生显著分化以形成蜕膜，这是一种支持胎儿生长的短暂母体组织。了解协调胎盘正常发育的关键蜕膜途径非常重要，胎盘是母胎界面的关键结构。我们发现，在条件性敲除小鼠模型中，蜕膜基质细胞中转录因子Runx1表达的缺失会导致胎盘形成过程中的胎儿死亡。进一步的表型分析表明，怀孕小鼠的子宫蜕膜血管生成严重受损，滋养层细胞分化和迁移缺乏，导致螺旋动脉重塑受损。使用敲除小鼠和对照小鼠的子宫进行基因表达谱分析发现，Runx1直接控制间隙连接蛋白连接蛋白43（也称为GJA1）的蜕膜表达，此前已证明该蛋白对蜕膜血管生成至关重要。我们的研究还表明，Runx1在妊娠早期控制胰岛素样生长因子（IGF）2和IGF结合蛋白4（IGFBP4）的表达。虽然Runx1缺乏会显著降低蜕膜细胞产生IGF2的量，但我们观察到IGFBP4的表达同时升高，IGFBP4调节IGF的生物利用度，从而控制滋养层细胞分化。我们认为，敲除小鼠蜕膜中GJA1、IGF2和IGFBP4的表达失调导致了观察到的子宫血管生成、滋养层细胞分化和血管重塑缺陷。因此，本研究为控制胎盘发育关键窗口期内母胎相互作用早期阶段的关键母体途径提供了独特见解。
