ABSTRACT

Pathological angiogenesis is a hallmark of several conditions including eye diseases, inflammatory diseases, and cancer. Stromal cells play a crucial role in regulating angiogenesis through the release of soluble factors or direct contact with endothelial cells. Here, we analysed the properties of the extracellular vesicles (EVs) released by bone marrow mesenchymal stromal cells (MSCs) and explored the possibility of using them to therapeutically target angiogenesis. We demonstrated that in response to pro-inflammatory cytokines, MSCs produce EVs that are enriched in TIMP-1, CD39 and CD73 and inhibit angiogenesis targeting both extracellular matrix remodelling and endothelial cell migration. We identified a novel anti-angiogenic mechanism based on adenosine production, triggering of A_2B adenosine receptors, and induction of NOX2-dependent oxidative stress within endothelial cells. Finally, in pilot experiments, we exploited the anti-angiogenic EVs to inhibit tumour progression in vivo. Our results identify novel pathways involved in the crosstalk between endothelial and stromal cell and suggest new therapeutic strategies to target pathological angiogenesis.

摘要

病理性血管生成是几种疾病的标志，包括眼部疾病，炎性疾病和癌症。基质细胞通过释放可溶性因子或直接与内皮细胞接触，在调节血管生成中起关键作用。在这里，我们分析了骨髓间充质基质细胞（MSCs）释放的细胞外囊泡（EVs）的特性，并探讨了使用它们治疗性地靶向血管生成的可能性。我们证明，响应促炎性细胞因子，MSC产生富含TIMP-1，CD39和CD73的EV，并抑制靶向细胞外基质重塑和内皮细胞迁移的血管生成。我们确定了一种基于腺苷产生，触发A _2B的新型抗血管生成机制腺苷受体，以及内皮细胞内NOX2依赖性氧化应激的诱导。最后，在先导实验中，我们利用抗血管生成电动车在体内抑制肿瘤的进展。我们的研究结果确定了内皮细胞与基质细胞之间串扰的新途径，并提出了针对病理性血管新生的新治疗策略。