Shu Junlan, Terakawa Jumpei, Takikawa Sota, Osuka Satoko, Muraoka Ayako, Ruan Jiali, Iida Atsuo, Ito Junya, Hondo Eiichi
Laboratory of Animal Morphology, Department of Animal Sciences, Graduate School of Bioagricultural Sciences, Nagoya University, Nagoya, 464-8601, Aichi, Japan.
Laboratory of Toxicology, School of Veterinary Medicine, Azabu University, Sagamihara, 252-5201, Kanagawa, Japan.
Sci Rep. 2025 Sep 9;15(1):32387. doi: 10.1038/s41598-025-18471-3.
During early pregnancy in mice, leukemia inhibitory factor (LIF) regulates embryo implantation by activating the JAK/STAT3 signaling pathway. The STAT3 pathway has been recognized to play a critical role in embryo implantation; however, it remains unclear whether STAT3 activation alone is sufficient to induce implantation. In this study, we investigated the effects of RO8191, a potential STAT3 activator, on embryo implantation through a series of studies with different mouse models. We found that RO8191 can induce embryo implantation and decidual reaction by activating STAT3, but not STAT1, signaling in both epithelial and stromal compartments in delayed implantation models. Furthermore, RO8191 was able to rescue implantation and establish pregnancy even in uterine epithelial-specific Lifr conditional knockout (cKO) mice, which exhibit infertility due to implantation failure. In contrast, in uterine epithelial-specific Stat3 or Gp130 conditional knockout (cKO) mice, which also show embryo implantation failure, RO8191 induces only a partial decidual response. These results suggest that STAT3, Gp130 and LIFR each play distinct roles in embryo implantation and development. Although the detailed mechanisms underlying RO8191's action remain to be elucidated, our findings provide insights supporting its potential application in treating recurrent implantation failure.
在小鼠妊娠早期，白血病抑制因子（LIF）通过激活JAK/STAT3信号通路来调节胚胎着床。STAT3通路已被认为在胚胎着床中起关键作用；然而，单独的STAT3激活是否足以诱导着床仍不清楚。在本研究中，我们通过一系列针对不同小鼠模型的研究，调查了潜在的STAT3激活剂RO8191对胚胎着床的影响。我们发现，RO8191可通过激活延迟着床模型上皮和基质区室中的STAT3而非STAT1信号，来诱导胚胎着床和蜕膜反应。此外，即使在子宫上皮特异性Lifr条件性敲除（cKO）小鼠中，RO8191也能够挽救着床并建立妊娠，这些小鼠因着床失败而表现出不育。相反，在同样表现出胚胎着床失败的子宫上皮特异性Stat3或Gp130条件性敲除（cKO）小鼠中，RO8191仅诱导部分蜕膜反应。这些结果表明，STAT3、Gp130和LIFR在胚胎着床和发育中各自发挥着不同的作用。尽管RO8191作用的详细机制仍有待阐明，但我们的研究结果为支持其在治疗反复着床失败中的潜在应用提供了见解。
