子宫腺肌病 z-bio 2025-08-26 3170

　　Adenomyosis refers to a disease caused by abnormal invasion of the endometrial tissue into the growth of the myometrium. The uterus itself contains two layers of key tissue: the inner layer is the endometrium (thickening and falling off with the menstrual cycle), and the outer layer is the uterine myometrium (the muscle layer that wraps the endometrium). After getting sick, the intimal tissue that invades the muscle layer will cause the surrounding muscle layer to thicken and the overall uterus to become larger. Patients often experience symptoms such as severe dysmenorrhea, excessive menstrual flow, and long-term pelvic pain. Some people may also face infertility problems, which has a great impact on their lives.

　　The treatment of this disease has always been limited. Either use non-steroidal anti-inflammatory drugs, hormone contraceptives, gonadotropin-releasing hormone agonists/antagonists, but there will be side effects such as hot flashes, decreased bone density, infertility, etc.; or simply cut the uterus, but it is not feasible for women who want to retain fertility.

　　Today we share a major research published in the top issue Signal Transduction and Targeted Therapy on August 13. It was led by Professor Xiao Ruiping, Researcher Hu Xinli of the School of Future Technology of Peking University and Professor Zhu Lan, Director of Obstetrics and Gynecology at Peking Union Medical College Hospital. It has brought breakthrough progress to the understanding and management of adenomyosis.

　　The research team collected endometrial samples from 13 women undergoing hysterectomy (7 without adenomyosis and 6 with adenomyosis). Single-cell RNA sequencing analysis was performed on more than 170,000 cells.

　　Analysis found that the subpopulation of "ECM-high epithelial cells" in patients with adenomyosis has increased significantly: this type of cells express epithelial cell marker (EPCAM) and fibroblast marker (DCN), showing a "double-sided" characteristic; and the proportion of this cell in patients with a disease course >2 years is higher, closer to the fibroblast characteristics. Gene set variation analysis (GSVA) shows that it is highly sensitive to various hormone signaling pathways such as estrogen and prolactin (PRL), among which prolactin receptor (PRLR) is particularly rich in expression.

　　PRL 信号功能验证实验

　　Through immunohistochemical staining, PRLR protein expression in the lesion tissues of patients with adenomyosis was significantly increased; however, enzyme-linked immunity and other methods were used to detect serum PRL levels, indicating that there was no significant difference between the patient and healthy controls, suggesting that the key to the disease lies in the overresponse of the tissue locally to PRL, rather than the increase in systemic PRL.

　　Proliferation experiment: Human primary endometrial epithelial cells (CPH-058) were cultured. After 48 hours of treatment at different concentrations of PRL, high-connotation live cell imaging counts were confirmed to promote cell proliferation in a dose-dependent manner.

　　Apoptosis experiment: Doxorubicin was used to induce apoptosis, and Caspase-3/7 activity was detected after adding different concentrations of PRL. The results showed that PRL significantly inhibited epithelial cell apoptosis. In the scRNA-seq data, the apoptosis score of AM_EC epithelial cells was reduced and TUNEL staining showed that the apoptosis signal of lesions was weaker than that of in situ endometrium, which clearly stated that PRL promoted lesions to expand through "pro-proliferation-inhibiting apoptosis".

　　成纤维细胞功能与细胞通讯分析

　　The study also focused on another key role in the tumor microenvironment - fibroblasts. Further analysis of fibroblast clustering was used to identify four subgroups: Fib_C7, ds1, ds2, and Pre-ds. Among them, "ds1 fibroblasts" have the highest inflammatory score in adenomyosis.

　　After culturing human endometrial stromal cells (hEM15A), 24 hours after PRL treatment, RT-qPCR detection showed a significant increase in inflammatory cytokine mRNA levels, confirming that PRL can enhance the inflammatory response of ds1 cells, which well explains the pain and fibrotic lesions associated with adenomyosis.

　　CellChat R package was used to analyze intercellular signal communication, and it was found that in patients with adenomyosis, the WNT and NOTCH signals between fibroblasts and epithelial cells (regulating the differentiation of epithelial cells during the menstrual cycle) were significantly weakened, and cell adhesion signals (such as JAM and CDH) were also downregulated, resulting in disorders of cell interactions and epithelial cells were more likely to invade the myometrium.

　　How to prove that PRLR is the key?

　　The research team conducted two sets of animal experiments:

　　A PRL transgenic mice with "prolactin overexpression" found that 80% of mice had the same symptoms as human adenomyosis (the endometrium drilled into the muscle layer), but normal mice did not.

　　A model of uterine horn pituitary transplantation: transplantation of 7-week-old pituitary glands of C57BL/6N mice to the renal envelope (RPT, systemic PRL elevation) or uterine horn (UPT, local PRL elevation). After observation at 2, 4, and 6 months after surgery, all UPT mice developed adenomyosis at 6 months, while only a few RPT mice showed pathological changes.

　　This shows that the PRL signal that is highly active in the uterus is the real "critical factor for pathogenicity".

　　Since PRL must pass through a "receiver", the research team used monoclonal antibody HMI-115 targeting RPL receptors to treat UPT model mice:

　　Early treatment: 2 weeks after surgery (without significant pathological changes), 30mg/kg HMI-115 (or control IgG) was injected weekly for 7 weeks for 7 weeks. The results showed that HMI-115 significantly reduced the incidence and severity of adenomyosis.

　　Advanced treatment: The administration was started 6 months after the operation (when the disease was established), and 30mg/kg HMI-115 was injected weekly for 7 weeks, and about 50% of the mice completely disappeared, and the treatment did not affect the weight and uterine weight of the mice, and its safety was initially confirmed.

　　Of course, there is still a long way to go from mouse experiments to becoming truly available drugs for patients. But this study undoubtedly lights up a hopeful beacon for countless women suffering from adenomyosis and is a model of translational medicine.