Changes in the micro-environment of fibrous connective tissue can lead to alterations in the phenotypes of tissue-resident cells, yet the underlying mechanisms are poorly understood. Here, by visualizing the dynamics of histone spatial reorganization in tenocytes and mesenchymal stromal cells from fibrous tissue of human donors via super-resolution microscopy, we show that physiological and pathological chemomechanical cues can directly regulate the spatial nanoscale organization and density of chromatin in these tissue-resident cell populations. Specifically, changes in substrate stiffness, altered oxygen tension and the presence of inflammatory signals drive chromatin relocalization and compaction into the nuclear boundary, mediated by the activity of the histone methyltransferase EZH2 and an intact cytoskeleton. In healthy cells, chemomechanically triggered changes in the spatial organization and density of chromatin are reversible and can be attenuated by dynamically stiffening the substrate. In diseased human cells, however, the link between mechanical or chemical inputs and chromatin remodelling is abrogated. Our findings suggest that aberrant chromatin organization in fibrous connective tissue may be a hallmark of disease progression that could be leveraged for therapeutic intervention.

纤维结缔组织微环境的变化可导致组织驻留细胞表型的改变，但其潜在机制尚不清楚。在这里，通过超分辨率显微镜观察来自人类供体纤维组织的肌腱细胞和间充质基质细胞中组蛋白空间重组的动态，我们表明生理和病理化学机械线索可以直接调节这些组织中染色质的空间纳米级组织和密度-常驻细胞群。具体而言，底物刚度的变化、氧张力的改变和炎症信号的存在会驱动染色质重新定位并压实到核边界，这是由组蛋白甲基转移酶 EZH2 的活性和完整的细胞骨架介导的。在健康细胞中，化学机械触发的染色质空间组织和密度的变化是可逆的，并且可以通过动态硬化基质来减弱。然而，在患病的人类细胞中，机械或化学输入与染色质重塑之间的联系被废除了。我们的研究结果表明，纤维结缔组织中的异常染色质组织可能是疾病进展的标志，可用于治疗干预。