Abstract
Tendons connect muscle to bone, enabling skeletal movement and joint stability. During natural aging, tendons exhibit impaired homeostasis, increased risk of injury and impaired healing capacity. Understanding the mechanisms responsible for maintenance of tendon homeostasis and how these mechanisms are diminished with aging is crucial for developing therapeutics that can inhibit age-related impairments in tendon function and healing capacity. Here we show that depletion of Scleraxis-lineage (ScxLin) cells, the predominant tenocyte population in adult tendons, recapitulates age-related impairments in cell density, ECM structure and organization. Proteomic analysis demonstrated comparable ECM compositional shifts with ScxLin depletion in young adult tendon, and wild type (WT) aged tendons and identify the specific ECM components that are lost during disrupted tendon homeostasis. Consistent with this, single cell RNA sequencing demonstrates loss of tenocyte subpopulations associated with “ECM synthesis” in both aging and ScxLin depletion, identifying the requirement for these cells in maintaining tendon homeostasis. However, aging and ScxLin depletion results in differential retention of other tenocyte populations, with retention of a specialized remodeling tenocyte population concomitant with mechanically superior healing in ScxLin depleted tendons relative to WT. In contrast, aged tendon retains a pro-inflammatory tenocyte population, which may drive the impaired healing outcomes observed during aging. Collectively, this study defines ScxLin cell depletion as a novel model of accelerated tendon ECM aging and identifies tenocyte subpopulations that are associated with disrupted tendon homeostasis and differential healing outcomes.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
↵* Indicates senior author