Scleraxis-lineage cells are required for tendon homeostasis and their depletion induces an accelerated extracellular matrix aging phenotype.
Scleraxis-lineage cells are required for tendon homeostasis and their depletion induces an accelerated extracellular matrix aging phenotype.
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DOI：
10.7554/elife.84194
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发表时间：
2023-01-19
期刊：
影响因子：
7.7
通讯作者：
Wan, Mei
中科院分区：
文献类型：
--
作者：
Korcari, Antonion;Nichols, Anne E. C.;Buckley, Mark R.;Loiselle, Alayna E.;Wan, Mei
老化的肌腱破坏了动态平衡，增加了受伤的风险，并损害了愈合能力。了解体内平衡紊乱的机制对于开发治疗方法以在整个生命周期内保持腱健康至关重要。在这里，我们发展了一种新的肌腱细胞外基质(ECM)老化模型(SCX-DTR)，该模型通过去除幼鼠的巩膜细胞系来加速肌腱细胞外基质(ECM)的老化。SCX-DTR总结了肌腱老化的许多方面，包括细胞密度的相应下降，细胞外基质结构、组织和成分的变化。单细胞RNA测序显示，在老年和SCX-DTR肌腱中，与ECM生物合成相关的肌腱细胞保守减少，确认了动态平衡期间对硬化轴系细胞的需求。然而，老年肌腱和SCX-DTR肌腱中的剩余细胞显示出功能分化。老化的肌腱细胞变得促炎，失去蛋白稳定。相反，来自SCX-DTR肌腱的肌腱细胞显示出增强的重塑能力。总而言之，本研究将SCX-DTR定义为一种加速肌腱ECM老化的新模型，并确定了新的生物干预点，以在整个寿命内维持肌腱功能。
Aged tendons have disrupted homeostasis, increased injury risk, and impaired healing capacity. Understanding mechanisms of homeostatic disruption is crucial for developing therapeutics to retain tendon health through the lifespan. Here, we developed a novel model of accelerated tendon extracellular matrix (ECM) aging via depletion of Scleraxis-lineage cells in young mice (Scx-DTR). Scx-DTR recapitulates many aspects of tendon aging including comparable declines in cellularity, alterations in ECM structure, organization, and composition. Single-cell RNA sequencing demonstrated a conserved decline in tenocytes associated with ECM biosynthesis in aged and Scx-DTR tendons, identifying the requirement for Scleraxis-lineage cells during homeostasis. However, the remaining cells in aged and Scx-DTR tendons demonstrate functional divergence. Aged tenocytes become pro-inflammatory and lose proteostasis. In contrast, tenocytes from Scx-DTR tendons demonstrate enhanced remodeling capacity. Collectively, this study defines Scx-DTR as a novel model of accelerated tendon ECM aging and identifies novel biological intervention points to maintain tendon function through the lifespan.