Kitawaki Yoshimi, Horie Akihito, Ikeda Asami, Shitanaka Shimpei, Yanai Akihiro, Ohara Tsutomu, Nakakita Baku, Sagae Yusuke, Okunomiya Asuka, Tani Hirohiko, Mandai Masaki
Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, 54 Shogoin Kawahara-Cho, Sakyo, Kyoto, 606-8507, Japan.
Department of Gynecology and Obstetrics, Medical Research Institute Kitano Hospital, 2-4-20 Ohgimachi, Kita-Ku, Osaka, 530-8480, Japan.
Cell Commun Signal. 2024 Dec 5;22(1):587. doi: 10.1186/s12964-024-01904-3.
Intrauterine peripheral blood mononuclear cell (PBMC) therapy for recurrent implantation failure (RIF) has been reported to improve embryo implantation by acting on the endometrium. However, the exact mode of action of PBMC on the endometrium of patients with RIF remains unclear. In addition, the differences in the therapeutic effects of PBMC therapy with and without human chorionic gonadotropin (hCG) are unknown. Therefore, in this study, we investigated the changes in the endometrium during the implantation phase induced by PBMC administration and the differences in the efficacy of this therapy with and without hCG using a mouse model of implantation failure (IF).
IF model was established by the subcutaneous administration of low-dose RU486. Pregnant mice were randomly divided into five groups: control, IF, culture medium, PBMC, and PBMC-hCG (the latter three groups were IF model mice with intrauterine administration). The pregnancy rate and the number and size of implantation sites were recorded during early pregnancy (day 7.5). Uteri from the preimplantation phase (evening of day 3.5) were collected and analyzed using RNA-sequencing (RNA-seq).
The pregnancy rate, the number of implantation sites, and the number of normal-sized implantation sites were significantly decreased in the IF model and were improved in the medium, PBMC, and PBMC-hCG groups. RNA-seq data showed that PBMC treatment normalized the expression of the majority of dysregulated genes in the endometrium during the preimplantation phase in the IF model, especially the overexpression of estrogen-activated genes. In addition, PBMC treatment increased the expression of local glucocorticoid receptors and suppressed the expression of inflammation-related genes, whereas no significant changes in blood estradiol and glucocorticoid levels were observed. These changes were more pronounced in the PBMC-hCG group and were consistent with the pregnancy outcomes.
Intrauterine administration of PBMC before embryo implantation promoted embryo implantation in the IF mouse model, and hCG enhanced pregnancy outcomes. PBMC modulated steroid receptor expression and suppressed inflammation and excessive estrogen action.
据报道，宫腔内注射外周血单个核细胞（PBMC）治疗反复种植失败（RIF）可通过作用于子宫内膜来改善胚胎着床。然而，PBMC对RIF患者子宫内膜的确切作用方式仍不清楚。此外，PBMC治疗联合或不联合人绒毛膜促性腺激素（hCG）的治疗效果差异尚不清楚。因此，在本研究中，我们使用种植失败（IF）小鼠模型，研究了PBMC给药后着床期子宫内膜的变化以及联合或不联合hCG治疗的疗效差异。
通过皮下注射低剂量米非司酮建立IF模型。将妊娠小鼠随机分为五组：对照组、IF组、培养基组、PBMC组和PBMC-hCG组（后三组为宫腔内给药的IF模型小鼠）。在妊娠早期（第7.5天）记录妊娠率、着床点数量和大小。收集着床前阶段（第3.5天晚上）的子宫，使用RNA测序（RNA-seq）进行分析。
IF模型的妊娠率、着床点数量和正常大小着床点数量显著降低，而培养基组、PBMC组和PBMC-hCG组有所改善。RNA-seq数据显示，PBMC治疗使IF模型着床前阶段子宫内膜中大多数失调基因的表达正常化，尤其是雌激素激活基因的过表达。此外，PBMC治疗增加了局部糖皮质激素受体的表达，抑制了炎症相关基因的表达，而血雌二醇和糖皮质激素水平未观察到显著变化。这些变化在PBMC-hCG组中更为明显，且与妊娠结局一致。
胚胎着床前宫腔内注射PBMC可促进IF小鼠模型的胚胎着床，hCG可提高妊娠结局。PBMC调节类固醇受体表达，抑制炎症和过度的雌激素作用。
