Abstract
IntroductionMacrophage-driven inflammation is a key feature of the early period following tendon repair, but excessive inflammation has been associated with poor clinical outcomes. Modulation of the inflammatory environment using molecular or cellular treatments may provide a means to enhance tendon healing.MethodsTo examine the effect of pro-inflammatory cytokines secreted by macrophages on tendon fibroblasts (TF), we established in vitro models of cytokine and macrophage-induced inflammation. Gene expression, protein expression, and cell viability assays were used to examine TF responses. In an effort to reduce the negative effects of inflammatory cytokines on TFs, adipose-derived mesenchymal stromal cells (ASCs) were incorporated into the model and their ability to modulate inflammation was investigated.ResultsThe inflammatory cytokine interleukin 1 beta (IL-1β) and macrophages of varying phenotypes induced up-regulation of pro-inflammatory factors and matrix degradation factors and down-regulation of factors related to extracellular matrix formation by TFs in culture. ASCs did not suppress these presumably negative effects induced by IL-1β. However, ASC co-culture with M1 (pro-inflammatory) macrophages successfully suppressed the effects of M1 macrophages on TFs by inducing a phenotypic switch from a pro-inflammatory macrophage phenotype to an anti-inflammatory macrophage phenotype, thus resulting in exposure of TFs to lower levels of pro-inflammatory cytokines (e.g., IL-1β, tumor necrosis factor alpha (TNFα)).ConclusionsThese findings suggest that IL-1β and M1 macrophages are detrimental to tendon healing and that ASC-mediated modulation of the post-operative inflammatory response may be beneficial for tendon healing.Electronic supplementary materialThe online version of this article (doi:10.1186/s13287-015-0059-4) contains supplementary material, which is available to authorized users.
Highlights
Macrophage-driven inflammation is a key feature of the early period following tendon repair, but excessive inflammation has been associated with poor clinical outcomes
Flow cytometry revealed that all macrophages expressed high levels of CD11b and F480, and that macrophages treated with M2-priming medium expressed high levels of CD206 and CD301 compared to M0 and M1 macrophages (Figure 1A)
mesenchymal stromal cells (MSC) did not have a demonstrable effect on interleukin 1 beta (IL-1β)-induced inflammation, implying that they neither modulate tendon fibroblasts (TF) responses to inflammation nor do they inactivate circulating IL-1β
Summary
Macrophage-driven inflammation is a key feature of the early period following tendon repair, but excessive inflammation has been associated with poor clinical outcomes. Despite advances in operative techniques and rehabilitation methods, the outcomes of treatment of tendon and tendon-to-bone repair are highly variable, resulting in a substantial clinical burden [1,2]. Recent evidence suggests that fine modulation of inflammation in the earliest stages following surgical repair may be required for improved outcomes [11,12,13,14]. Low levels of inflammatory cytokines are likely necessary to attract fibroblasts to the repair site [15,16], excessive inflammation after tendon repair has been identified as a key factor leading to poor clinical outcomes [11,13,14,17]. As pro-inflammatory M1 macrophages have been implicated in the poor healing
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