Extrinsic Macrophages Protect While Tendon Progenitors Degrade: Insights from a Tissue Engineered Model of Tendon Compartmental Crosstalk

Tendons are among the most mechanically stressed tissues of the body, with a functional core of type-I collagen fibers maintained by embedded stromal fibroblasts known as tenocytes. The intrinsic load-bearing core compartment of tendon is surrounded, nourished, and repaired by the extrinsic peritendon, a synovial-like tissue compartment with access to tendon stem/progenitor cells as well as blood monocytes. In vitro tendon model systems generally lack this important feature of tissue compartmentalization, while in vivo models are cumbersome when isolating multicellular mechanisms. To bridge this gap, an improved in vitro model of explanted tendon core stromal tissue (mouse tail tendon fascicles) surrounded by cell-laden collagen hydrogels that mimic extrinsic tissue compartments is suggested. Using this model, CD146(+) tendon stem/progenitor cell and CD45(+)F4/80(+) bone-marrow derived macrophage activity within a tendon injury-like niche are recapitulated. It is found that extrinsic stromal progenitors recruit to the damaged core, contribute to an overall increase in catabolic ECM gene expression, and accelerate the decrease in mechanical properties. Conversely, it is found that extrinsic bone-marrow derived macrophages in these conditions adopt a proresolution phenotype that mitigates rapid tissue breakdown by outwardly migrated tenocytes and F4/80(+) tenophages from the intrinsic tissue core.

Automated summary

Tendons are composed of a functional core of type-I collagen fibers maintained by tenocytes, surrounded by an extrinsic peritendon that contains stem/progenitor cells and blood monocytes. An in vitro model using explanted tendon core stromal tissue surrounded by cell-laden collagen hydrogels is suggested to bridge the gap between in vitro and in vivo models. This model replicates the recruitment of stromal progenitors to the damaged core, leading to an increase in gene expression for tissue degradation, while extrinsic bone-marrow derived macrophages adopt a proresolution phenotype to mitigate tissue breakdown.