Scleraxis-lineage cells are required for tendon homeostasis and their depletion induces an accelerated extracellular matrix aging phenotype.
Antonion KorcariAnne E C NicholsMark R BuckleyAlayna E LoisellePublished in: eLife (2023)
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.
Keyphrases
- extracellular matrix
- induced apoptosis
- single cell
- cell cycle arrest
- anterior cruciate ligament reconstruction
- randomized controlled trial
- rotator cuff
- public health
- oxidative stress
- mental health
- signaling pathway
- dna methylation
- magnetic resonance imaging
- genome wide
- adipose tissue
- gene expression
- transcription factor
- high throughput
- pi k akt
- skeletal muscle
- insulin resistance
- middle aged