Matrix stiffness regulates profibrotic fibroblast differentiation and fibrotic niche activation in systemic sclerosis.

IF 20.3 1区 医学 Q1 RHEUMATOLOGY
Ludwig Ueberall, Hashem Mohammadian, Richard Demmler, Yuko Ariza, Philipp Tripal, Charles Gwellem Anchang, Stefanie Weber, Mario Raphael Angeli, Maria Gabriella Raimondo, Jiyang Chang, Kaiyue Huang, Jörg H W Distler, Oliver Distler, Simon Rauber, Georg Schett, Andreas Ramming, Alina Mihaela Ramming
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引用次数: 0

Abstract

Objectives: Fibrosis progression in systemic sclerosis (SSc) has been attributed to matrix stiffness. Despite extensive research on fibroblast heterogeneity and subset imbalances in fibrotic disorders, the interplay between biomechanical cues and fibroblast dynamics remains largely unexplored. Here, we investigate how matrix stiffness alters fibroblast transcriptional state and influences lineage specification in fibrotic skin.

Methods: We employed a collagen I-based 3-dimensional culture system to expose fibroblasts to varying levels of matrix stiffness, followed by RNA sequencing to identify stiffness-responsive gene expression signature. We integrated single-cell RNA sequencing data from SSc and healthy skin samples to identify fibroblast subsets associated with this signature. Spatial transcriptomic analyses were performed to localise these fibroblasts and their associations with the fibrotic niche.

Results: Fibroblasts subjected to increased matrix stiffness exhibited a distinct transcriptional signature, amplified in SSc patients and enriched in PI16+ progenitor-like cells within the SFRP2+ fibrotic compartment. Further analysis indicated that PI16+ fibroblasts are predisposed to SFRP2+COMP+ PU.1+ myofibroblasts differentiation, whereas blocking mechanotransduction by focal adhesion kinase inhibition disrupts this process, suggesting that matrix stiffness is a key driver of this lineage transition. Spatial mapping revealed colocalisation of the PI16+ and COMP+ subsets in extracellular matrix-dense regions, highlighting the functional relevance of this relationship in fibrotic progression.

Conclusions: Our findings suggest that increased matrix stiffness promotes fibroblast precursor differentiation into SFRP2+ COMP+ PU.1+ myofibroblasts, thereby sustaining the vicious cycle of persistent fibrosis in absence of inflammatory triggers. These insights reveal new aspects of fibrosis pathogenesis and highlight biomechanical signals as therapeutic targets in SSc.

基质硬度调节系统性硬化症中原纤维化成纤维细胞分化和纤维化生态位激活。
目的:系统性硬化症(SSc)的纤维化进展归因于基质僵硬。尽管对纤维化疾病中的成纤维细胞异质性和亚群失衡进行了广泛的研究,但生物力学线索和成纤维细胞动力学之间的相互作用在很大程度上仍未被探索。在这里,我们研究基质硬度如何改变成纤维细胞转录状态并影响纤维化皮肤的谱系规范。方法:我们采用基于胶原i的三维培养系统,将成纤维细胞暴露于不同水平的基质刚度中,然后通过RNA测序来鉴定刚度响应基因表达特征。我们整合了来自SSc和健康皮肤样本的单细胞RNA测序数据,以鉴定与该特征相关的成纤维细胞亚群。空间转录组学分析用于定位这些成纤维细胞及其与纤维化生态位的关联。结果:基质硬度增加的成纤维细胞表现出明显的转录特征,在SSc患者中扩增,并在SFRP2+纤维化室中的PI16+祖细胞样细胞中富集。进一步的分析表明,PI16+成纤维细胞倾向于SFRP2+COMP+ PU.1+肌成纤维细胞分化,而通过局灶粘附激酶抑制阻断机械转导会破坏这一过程,这表明基质刚度是这一世系转变的关键驱动因素。空间定位揭示了PI16+和COMP+亚群在细胞外基质密集区域的共定位,强调了这种关系在纤维化进展中的功能相关性。结论:我们的研究结果表明,增加的基质硬度促进成纤维细胞前体分化为SFRP2+ COMP+ PU.1+肌成纤维细胞,从而在没有炎症触发的情况下维持持续纤维化的恶性循环。这些见解揭示了纤维化发病机制的新方面,并强调了生物力学信号作为SSc的治疗靶点。
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来源期刊
Annals of the Rheumatic Diseases
Annals of the Rheumatic Diseases 医学-风湿病学
CiteScore
35.00
自引率
9.90%
发文量
3728
审稿时长
1.4 months
期刊介绍: Annals of the Rheumatic Diseases (ARD) is an international peer-reviewed journal covering all aspects of rheumatology, which includes the full spectrum of musculoskeletal conditions, arthritic disease, and connective tissue disorders. ARD publishes basic, clinical, and translational scientific research, including the most important recommendations for the management of various conditions.
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