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脂肪间充质干细胞通过调节细胞焦亡和促进组织修复来稳定盆底损伤免疫微环境的机制。

The mechanism of adipose mesenchymal stem cells to stabilize the immune microenvironment of pelvic floor injury by regulating pyroptosis and promoting tissue repair.

作者信息

Wu Xiaotong, Zhang Fengshi, Mao Xiaolin, Xu Fujian, Ding Xiaokang, Sun Xiuli, Wang Jianliu

机构信息

Department of Obstetrics and Gynecology, Peking University People's Hospital, 100044, Beijing, China.

Beijing Key Laboratory of Female Pelvic Floor Disorders, 100044, Beijing, China.

出版信息

Mater Today Bio. 2023 Dec 18;24:100910. doi: 10.1016/j.mtbio.2023.100910. eCollection 2024 Feb.

Abstract

Pelvic organ prolapse (POP) has a high incidence rate among Chinese women. Repeated mechanical stimulation is an important factor causing POP, but the injury mechanism has not yet been elucidated. The purpose of this study is to explore the related mechanisms of pelvic floor supporting tissue damage caused by mechanical force and the application of stem cell therapy. First, we obtained vaginal wall and sacral ligament tissue samples from clinical patients for examination. Pelvic floor support tissues of POP patients displayed high expression of inflammation and immune disorders. Then, we constructed a rat model of childbirth injury. In vivo and in vitro experiments investigated the key mechanism of pelvic floor support tissue injury caused by mechanical force. We discovered that after mechanical force, a large number of reactive oxygen species (ROS) and macrophages rapidly accumulated in pelvic floor tissues. ROS stimulated macrophages to produce NLRP3 inflammatory complex, induced the release of interleukin (IL-1β) and pyroptosis and exacerbated the inflammatory state of damaged tissues, persisting chronic inflammation of fibroblasts in supporting tissues, thus causing the pelvic floor's extracellular matrix (ECM) collagen metabolic disorder. Resultingly impeding the repair process, thereby causing the onset and progression of the disease. Through their paracrine ability, we discovered that adipose mesenchymal stem cells (ADSCs) could inhibit this series of pathological processes and promote tissue repair, asserting a good therapeutic effect. Simultaneously, to overcome the low cell survival rate and poor therapeutic effect of directly injecting cells, we developed a ROS-responsive PVA@COLI hydrogel with ADSCs. The ROS-scavenging properties of the gel could reshape the site of inflammation injury, enhance cell survival, and play a role in subsequent treatment. The findings of this study could serve as a basis for early, targeted intervention therapy for POP and representing a promising approach.

摘要

盆腔器官脱垂(POP)在中国女性中发病率较高。反复的机械刺激是导致POP的重要因素,但其损伤机制尚未阐明。本研究旨在探讨机械力引起盆底支持组织损伤的相关机制以及干细胞治疗的应用。首先,我们从临床患者获取阴道壁和骶韧带组织样本进行检测。POP患者的盆底支持组织表现出炎症和免疫紊乱的高表达。然后,我们构建了分娩损伤大鼠模型。体内和体外实验研究了机械力引起盆底支持组织损伤的关键机制。我们发现,在机械力作用后,大量活性氧(ROS)和巨噬细胞迅速在盆底组织中积累。ROS刺激巨噬细胞产生NLRP3炎性小体,诱导白细胞介素(IL-1β)释放和细胞焦亡,并加剧受损组织的炎症状态,使支持组织中的成纤维细胞持续慢性炎症,从而导致盆底细胞外基质(ECM)胶原代谢紊乱。结果阻碍了修复过程,进而导致疾病的发生和发展。通过其旁分泌能力,我们发现脂肪间充质干细胞(ADSCs)可以抑制这一系列病理过程并促进组织修复,显示出良好的治疗效果。同时,为了克服直接注射细胞时细胞存活率低和治疗效果差的问题,我们开发了一种含有ADSCs的ROS响应性PVA@COLI水凝胶。该凝胶的ROS清除特性可以重塑炎症损伤部位,提高细胞存活率,并在后续治疗中发挥作用。本研究结果可为POP的早期靶向干预治疗提供依据,并代表一种有前景的方法。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5324/10776425/b4038d4b8c81/ga1.jpg

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