Heinmäe Elizabeth, Mäemets-Allas Kristina, Maasalu Katre, Vastšjonok Darja, Klaas Mariliis
Institute of Molecular and Cell Biology, University of Tartu, Riia 23b, 51010 Tartu, Estonia.
Department of Cell and Molecular Biology, Karolinska Institute, 171 77 Stockholm, Sweden.
Int J Mol Sci. 2025 Mar 28;26(7):3146. doi: 10.3390/ijms26073146.
Dupuytren's contracture belongs to a group of fibrotic diseases that have similar mechanisms but lack effective treatment and prevention options. The excessive accumulation of connective tissue in Dupuytren's disease leads to palmar fibrosis that results in contracture deformities. The present study aimed to investigate how the tissue microenvironment in Dupuytren's contracture affects the phenotypic differentiation of macrophages, which leads to an inflammatory response and the development of chronicity in fibrotic disease. We utilized a decellularization-based method combined with proteomic analysis to identify shifts in extracellular matrix composition and the surrounding tissue microenvironment. We found that the expression of several matricellular proteins, such as MFAP4, EFEMP1 (fibulin-3), and ANGPTL2, was elevated in Dupuytren's tissue. We show that, in response to the changes in the extracellular matrix of Dupuytren's contracture, macrophages regulate the fibrotic process by cytokine production, promote myofibroblast differentiation, and increase the fibroblast migration rate. Moreover, we found that the extracellular matrix of Dupuytren's contracture directly supports the macrophage-to-myofibroblast transition, which could be another contributor to Dupuytren's disease pathogenesis. Our results suggest that interactions between macrophages and the extracellular matrix should be considered as targets for novel fibrotic disease treatment and prevention strategies in the future.
杜普伊特伦挛缩症属于一类纤维化疾病，它们具有相似的发病机制，但缺乏有效的治疗和预防方法。在杜普伊特伦病中，结缔组织的过度积累会导致手掌纤维化，进而导致挛缩畸形。本研究旨在探讨杜普伊特伦挛缩症中的组织微环境如何影响巨噬细胞的表型分化，这会导致炎症反应以及纤维化疾病的慢性发展。我们采用了一种基于脱细胞的方法并结合蛋白质组学分析，以确定细胞外基质组成和周围组织微环境的变化。我们发现，在杜普伊特伦组织中，几种基质细胞蛋白的表达升高，如MFAP4、EFEMP1（纤连蛋白-3）和ANGPTL2。我们表明，巨噬细胞响应杜普伊特伦挛缩症细胞外基质的变化，通过细胞因子产生来调节纤维化过程，促进肌成纤维细胞分化，并提高成纤维细胞迁移率。此外，我们发现杜普伊特伦挛缩症的细胞外基质直接支持巨噬细胞向肌成纤维细胞的转变，这可能是杜普伊特伦病发病机制的另一个促成因素。我们的结果表明，巨噬细胞与细胞外基质之间的相互作用应被视为未来新型纤维化疾病治疗和预防策略的靶点。
