Department of Mechanical Engineering, Orthopaedic Bioengineering Research Laboratory, Colorado State University, Fort Collins, Colorado, USA.
Department of Clinical Sciences, Animal Reproduction and Biotechnology Laboratory, Colorado State University, Fort Collins, Colorado, USA.
Tissue Eng Part A. 2023 May;29(9-10):282-291. doi: 10.1089/ten.TEA.2022.0185. Epub 2023 Mar 27.
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 by scratch-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. These data 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 Statement Adipose-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.
肌腱损伤和疾病对手术修复有抵抗力；因此，广泛研究了辅助疗法，特别是间充质基质细胞（MSCs），以及最近的细胞外囊泡（MSCdEVs），例如外泌体。MSCdEVs 被认为作用于驻留和浸润的免疫细胞，其旁分泌信号的作用引起了极大的关注。本研究探讨了 MSCdEVs 与来源于驻留（腱细胞）群体的类似物（TdEV）有何不同。由于巨噬细胞在肌腱维持和修复中起着重要作用，因此通过使用多重免疫分析的细胞因子定量和划痕愈合分析比较了巨噬细胞信号。与使用 MSCdEVs 替代 TdEVs 相比，TdEV 处理的巨噬细胞减少了 IL-1 的表达，增加了 MIP-1 和 CXCL8 的表达。此外，巨噬细胞信号有利于胶原蛋白合成和腱细胞生物活性，同时减少了促血管生成信号。这些数据表明，根据细胞来源，外泌体对巨噬细胞信号的影响存在差异，支持局部细胞来源的外泌体可能通过不同的方式优先促进愈合，与 MSCdEVs 相比可能具有不同的结果。 影响陈述 脂肪来源的间充质基质细胞（AdMSC）外泌体（EVs）可以改善肌腱的机械弹性、组织组织和对肌腱损伤的 M2 巨噬细胞表型优势。这一活跃的研究领域激发了人们对这些外泌体作为肌腱疾病辅助治疗的功能的极大兴趣，特别是肩袖肌腱病。然而，对于 EVs 作为细胞来源的功能，以及它们在临床前转化羊模型中的疗效，知之甚少。在此，我们证明了外泌体作为细胞来源的功能的差异效应，与 tenocyte 相比，AdMSCs 对巨噬细胞信号和绵羊细胞的迁移有影响。
