BACKGROUND Fibrosis is an important pathological feature of endometriotic lesions of all subtypes. Fibrosis is present in and around endometriotic lesions, and a central role in its development is played by myofibroblasts, which are cells derived mainly after epithelial-to-mesenchymal transition (EMT) and fibroblast-to-myofibroblast transdifferentiation (FMT). Transforming growth factor-β (TGF-β) has a key role in this myofibroblastic differentiation. Myofibroblasts deposit extracellular matrix (ECM) and have contracting abilities, leading to a stiff micro-environment. These aspects are hypothesized to be involved in the origin of endometriosis-associated pain. Additionally, similarities between endometriosis-related fibrosis and other fibrotic diseases, such as systemic sclerosis or lung fibrosis, indicate that targeting fibrosis could be a potential therapeutic strategy for non-hormonal therapy for endometriosis. OBJECTIVE AND RATIONALE This review aims to summarize the current knowledge and to highlight the knowledge gaps about the role of fibrosis in endometriosis. A comprehensive literature overview about the role of fibrosis in endometriosis can improve the efficiency of fibrosis-oriented research in endometriosis. SEARCH METHODS A systematic literature search was performed in three biomedical databases using search terms for 'endometriosis', 'fibrosis', 'myofibroblasts', 'collagen', and 'α-smooth muscle actin'. Original studies were included if they reported about fibrosis and endometriosis. Both preclinical in vitro and animal studies, as well as research concerning human subjects were included. OUTCOMES Our search yielded 3441 results, of which 142 studies were included in this review. Most studies scored a high to moderate risk of bias according to the bias assessment tools. The studies were divided in three categories: human observational studies, experimental studies with human-derived material, and animal studies. The observational studies showed details about the histologic appearance of fibrosis in endometriosis and the co-occurrence of nerves and immune cells in lesions. The in vitro studies identified several pro-fibrotic pathways in relation to endometriosis. The animal studies mainly assessed the effect of potential therapeutic strategies to halt or regress fibrosis, for example targeting platelets or mast cells. WIDER IMPLICATIONS This review shows the central role of fibrosis and its main cellular driver, the myofibroblast, in endometriosis. Platelets and TGF-β have a pivotal role in pro-fibrotic signaling. The presence of nerves and neuropeptides is closely associated with fibrosis in endometriotic lesions, and is likely a cause of endometriosis-associated pain. The process of fibrotic development after EMT and FMT shares characteristics with other fibrotic diseases, so exploring similarities in endometriosis with known processes in diseases like systemic sclerosis, idiopathic pulmonary fibrosis or liver cirrhosis is relevant and a promising direction to explore new treatment strategies. The close relationship with nerves appears rather unique for endometriosis-related fibrosis and is not observed in other fibrotic diseases. REGISTRATION NUMBER N/A.

中文翻译：

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纤维化在子宫内膜异位症中的作用：系统评价。


背景 纤维化是所有亚型子宫内膜异位病变的重要病理特征。纤维化存在于子宫内膜异位病变内部和周围，肌成纤维细胞在其发展中起着核心作用，肌成纤维细胞是主要在上皮-间充质转化 （EMT） 和成纤维细胞到肌成纤维细胞转分化 （FMT） 后衍生的细胞。转化生长因子-β （TGF-β） 在这种肌成纤维细胞分化中起关键作用。肌成纤维细胞沉积细胞外基质 （ECM） 并具有收缩能力，导致僵硬的微环境。据推测，这些方面与子宫内膜异位症相关疼痛的起源有关。此外，子宫内膜异位症相关纤维化与其他纤维化疾病（如系统性硬化症或肺纤维化）之间的相似性表明，靶向纤维化可能是子宫内膜异位症非激素治疗的潜在治疗策略。目标和基本原理 本综述旨在总结目前的知识，并强调关于纤维化在子宫内膜异位症中的作用的知识差距。关于纤维化在子宫内膜异位症中的作用的全面文献综述可以提高子宫内膜异位症中以纤维化为导向的研究的效率。检索方法 使用“子宫内膜异位症”、“纤维化”、“肌成纤维细胞”、“胶原蛋白”和“α-平滑肌肌动蛋白”的检索词在三个生物医学数据库中进行了系统的文献检索。如果原始研究报告了纤维化和子宫内膜异位症，则纳入原始研究。包括临床前体外和动物研究，以及有关人类受试者的研究。结果 我们的检索产生了 3441 个结果，其中 142 项研究被纳入本综述。 根据偏倚评估工具，大多数研究的偏倚风险分为高到中等。这些研究分为三类：人类观察研究、使用人类来源材料的实验研究和动物研究。观察性研究显示了子宫内膜异位症中纤维化的组织学表现以及病变中神经和免疫细胞共存的细节。体外研究确定了几种与子宫内膜异位症相关的促纤维化途径。动物研究主要评估了阻止或消退纤维化的潜在治疗策略的效果，例如靶向血小板或肥大细胞。更广泛的意义 本综述显示了纤维化及其主要细胞驱动因素肌成纤维细胞在子宫内膜异位症中的核心作用。血小板和 TGF-β 在促纤维化信号传导中起关键作用。神经和神经肽的存在与子宫内膜异位病变的纤维化密切相关，并且可能是子宫内膜异位症相关疼痛的原因。EMT 和 FMT 后纤维化发展的过程与其他纤维化疾病具有共同特征，因此探索子宫内膜异位症与系统性硬化症、特发性肺纤维化或肝硬化等疾病的已知过程的相似性是相关的，并且是探索新治疗策略的有前途的方向。对于子宫内膜异位症相关的纤维化来说，与神经的密切关系似乎相当独特，在其他纤维化疾病中未观察到。注册号 N/A。