Primary Human Macrophage and Tenocyte Tendon Healing Phenotypes Changed by Exosomes Per Cell Origin

The high failure rate of surgical repair for tendinopathies has spurred interest in adjunct therapies, including exosomes (EVs). Mesenchymal stromal cell (MSC)-derived EVs (MSCdEVs) have been of particular interest as they improve several metrics of tendon healing in animal models. However, research has shown that EVs derived from tissue-native cells, such as tenocytes, are functionally distinct and may better direct tendon healing. To this end, we investigated the differential regulation of human primary macrophage transcriptomic responses and cytokine secretion by tenocyte-derived EVs (TdEVs) compared with MSCdEVs. Compared with MSCdEVs, TdEVs upregulated TNFa-NFkB and TGFB signaling and pathways associated with osteoclast differentiation in macrophages while decreasing secretion of several pro-inflammatory cytokines. Conditioned media of these TdEV educated macrophages drove increased tenocyte migration and decreased MMP3 and MMP13 expression. In contrast, MSCdEV education of macrophages drove increased gene expression pathways related to INFa, INFg and protection against oxidative stress while increasing cytokine expression of MCP1 and IL6. These data demonstrate that EV cell source differentially impacts the function of key effector cells in tendon healing and that TdEVs, compared with MSCdEVs, promote a more favorable tendon healing phenotype within these cells.