恒河猴自发性盆腔器官脱垂作为研究人盆腔器官脱垂理想模型的综合评价

A comprehensive evaluation of spontaneous pelvic organ prolapse in rhesus macaques as an ideal model for the study of human pelvic organ prolapse

盆腔器官脱垂严重影响女性的生活质量且其治疗的并发症严重.开发新疗法须在临床前研究中对其免疫反应和安全性进行评估.但多数四足动物的解剖结构和病理变化与人相差较大,目前缺乏合适的动物模型.本研究对72只老年恒河猴进行了体格检查,发现恒河猴自发性盆腔器官脱垂的发生率与人相似.作者选取了5只正常恒河猴和4只脱垂恒河猴的阴道组织进行进一步分析.Verhoeff-van Gieson染色表明,与正常恒河猴相比,恒河猴脱垂阴道的弹力纤维含量明显降低.免疫组化结果表明,恒河猴脱垂阴道的平滑肌束紊乱,大平滑肌束的数量明显低于正常恒河猴.天狼星红染色提示恒河猴脱垂阴道中Ⅰ型和Ⅲ型?原蛋白的比值明显降低.恒河猴脱垂阴道的组织学形态和生化改变与人脱垂相似.作者进一步构建了恒河猴脱垂后阴道的单细胞转录组图谱,对比分析显示人和恒河猴的阴道具有相似的细胞组成.差异基因分析提示细胞外基质失调和免疫紊乱是保守的分子机制.成纤维细胞和巨噬细胞的相互作用可能在人和恒河猴脱垂中都起到重要作用.综上,该研究对恒河猴自发性脱垂进行了综合评估并表明其是盆腔器官脱垂研究的合适动物模型.

Pelvic organ prolapse(POP)seriously affects a woman’s quality of life,and the treatment complications are severe.Although new surgical treatments are being developed,the host tissue responses and safety need to be evaluated in preclinical trials.However,there is a lack of suitable animal models,as most quadrupeds exhibit different structural and pathological changes.In this study,72 elderly rhesus macaques(Macaca mulatta)were physically examined,and the incidence of spontaneous POP was similar to that in humans.The vaginal wall from five control monkeys and four monkeys with POP were selected for further analysis.Verhoeff-van Gieson staining showed that elastin content decreased significantly in monkeys with POP compared with control samples.Immunohistological staining revealed that the smooth muscle bundles in monkey POP appeared disorganized,and the number of large muscle bundles decreased significantly.The collagen Ⅰ/Ⅲ ratio in monkey POP also significantly decreased,as revealed by Sirius Red staining.These histological and biochemical changes in monkeys with POP were similar to those in humans with POP.Moreover,we generated a single-cell transcriptomic atlas of the prolapsed monkey vagina.Cross-species analysis between humans and monkeys revealed a comparable cellular composition.Notably,a differential gene expression analysis determined that dysregulation of the extracellular matrix and an immune disorder were the conserved molecular mechanisms.The interplay between fibroblasts and macrophages contributed to human and monkey POP.Overall,this study represents a comprehensive evaluation of spontaneous POP in rhesus macaques and demonstrates that monkeys are a suitable animal model for POP research.