Abstract
ABSTRACTTendon disorders frequently occur and recent evidence has clearly implicated the presence of immune cells and inflammatory events during early tendinopathy. However, the origin and properties of these cells remain poorly defined. Therefore, the aim of this study was to determine the presence of cells in healthy rodent and human tendon tissue fulfilling macrophage-like functions. Using various transgenic reporter mouse models, we demonstrate the presence of tendon-resident cells in the dense matrix of the tendon core expressing the fractalkine (Fkn) receptor CX3CR1 and its cognate ligand CX3CL1/Fkn. Pro-inflammatory stimulation of 3D tendon-like constructs in vitro resulted in a significant increase in the expression of IL-1β, IL-6, Mmp3, Mmp9, CX3CL1 and epiregulin, which has been reported to contribute to inflammation, wound healing and tissue repair. Furthermore, we demonstrate that inhibition of the Fkn receptor blocked tendon cell migration in vitro, and show the presence of CX3CL1/CX3CR1/EREG-expressing cells in healthy human tendons. Taken together, we demonstrate the presence of CX3CL1+/CX3CR1+ ‘tenophages’ within the healthy tendon proper, which potentially fulfill surveillance functions in tendons.This article has an associated First Person interview with the first author of the paper.
Highlights
Tendon pathologies and injuries are one of the most common musculoskeletal disorders, due to the tissue’s poor regenerative capacity the healing process is long-lasting and outcomes are often not satisfactory
Summary Statement: Here, we demonstrate the presence of a macrophage-like, CX3CL1/CX3CR1-expressing tendon cell population within the healthy tendon proper potentially fulfilling a surveillance function
The aim of this study was to determine the presence of cells in healthy rodent and human tendon tissue fulfilling macrophage-like functions
Summary
Tendon pathologies and injuries are one of the most common musculoskeletal disorders, due to the tissue’s poor regenerative capacity the healing process is long-lasting and outcomes are often not satisfactory. Gaining a deeper insight into the nature and function of tendon-resident cells in tissue homeostasis and disease is imperative for developing new treatment strategies for tendinopathies. The presence of myeloid and lymphoid cells such as mast cells, T cells, and macrophages during early human tendinopathy highlight a role of inflammation in tendon disease (Dean et al, 2016; Kragsnaes et al, 2014; Millar et al, 2010). Tissue-resident macrophages in vivo are not a homogeneous cell population, but heterogeneous in nature and respond to certain stimuli with overlapping functions and phenotypes and often can not be classified into simple, polarized categories (Davies and Taylor, 2015). The presence and distribution of cells fulfilling macrophage- or monocyte-related functions in healthy tendons has not been thoroughly investigated so far and due to the hypovascular nature of tendons, we hypothesize that in tendons these cells are present in the perivascular region, and reside within the dense, collagen-rich tendon core fulfilling a surveillance function similar to Langerhans cells in the skin or microglia in the brain (Deckers et al, 2018; Lehner et al, 2016)
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