Tendon injuries and disease are resistant to surgical repair; thus, adjunct therapies are widely investigated, especially mesenchymal stromal cells (MSCs) and, more recently, their extracellular vesicles (MSCdEVs), for example, exosomes. Thought to act on resident and infiltrating immune cells, the role of MSCdEVs in paracrine signaling is of great interest. This study investigated how MSCdEVs differ from analogs derived from resident (tenocyte) populations (TdEV). As macrophages play a significant role in tendon maintenance and repair, macrophage signaling was compared by cytokine quantification using a multiplexed immunoassay and tenocyte migration byin vitroscratch-wound analysis. TdEV-treated macrophages decreased IL-1 and increased MIP-1 and CXCL8 expression. In addition, macrophage signaling favored collagen synthesis and tenocyte bioactivity, while reducing proangiogenic signaling when TdEVs were used in place of MSCdEVs. Thesein vitrodata demonstrate a differential influence of exosomes on macrophage signaling, according to cell source, supporting that local cell-derived exosomes may preferentially drive healing by different means with possible different outcomes compared to MSCdEVs.Impact StatementAdipose-derived mesenchymal stromal cell (AdMSC) exosomes (EVs) can improve tendon mechanical resilience, tissue organization, and M2 macrophage phenotype predominance in response to tendon injury. This active area of investigation drives great interest in the function of these exosomes as adjunct therapies for tendon disease, particularly rotator cuff tendinopathy. However, little is known about the effects of EVs as a function of cell source, nor regarding their efficacy in preclinical translational ovine models. Herein we demonstrate a differential effect of exosomes as a function of cell source, tenocyte compared to AdMSCs, on macrophage signaling and tenocyte migration of ovine cells.