Mechanisms of extracellular vesicle biogenesis that regulate wound healing

总结 皮肤伤口愈合的解决是由细胞间通讯过程协调的， 包括含有生物活性蛋白质和核酸细胞外囊泡（EV）。在伤 在模型中，EV已被证明是组织修复的重要介质，尽管 形成特定EV子集的潜在机制，EV有效载荷的加载，以及细胞- 型特异性EV摄取仍然知之甚少。我们通过以下方式解决这一知识差距： 综合遗传学方法来修改EV生物发生的调节以改变EV 具有明确生物学特性的皮肤伤口模型中的特征、有效载荷和活性 本案无关我们最近已经确定，调控EV生物发生的遗传工具“重新编程” 电动车有效载荷。此外，过度表达特定的促修复有效载荷， 可以设计和交付，以促进模型的分辨率， 伤口愈合受损重点是发现新的串扰EV介质 之间的免疫和上皮细胞的伤口床，我们已经集中在生物学的电动汽车在 在EV形成中介导细胞间信号传导（项目1-EV生物发生）， 生物活性有效载荷（项目2-EV有效载荷），并确定特定的细胞类型， 在创面中内化EV（项目3-EV摄取）。这些项目共同解决了 通过优化的系统方法创建治疗性EV的过度目标， 具体的细胞类型，基于对1）如何以及在哪里制造电动汽车的理解？2)电动汽车如何 是否负载以及它们是否具有生物活性？;和3）哪些细胞摄取EV以促进 持久的组织修复

SUMMARY Resolution in skin wound healing is coordinated by intercellular communication processes that include extracellular vesicles (EVs) containing biologically active protein and nucleic acid. In injury models, EVs have been shown to be important mediators of tissue repair, although the mechanisms underlying the formation of specific EV subsets, loading of EV payloads, and cell- type specific EV uptake remain poorly understood. We address this knowledge gap with a comprehensive genetic approach to modify the regulation of EV biogenesis to change the EV Profile, Payload and Activity in cutaneous wound models that have well-defined biological relevance. We have recently established that genetic tools regulating EV biogenesis `re-program' EV payload. Moreover, over-expression of specific pro-reparative payloads that were identified by mass spectrometry can be engineered and delivered to promote resolution in models of impaired wound healing. With a focus on the discovery of novel EV mediators of crosstalk between immune and epithelial cells in the wound bed, we have focused on the biology of EVs in mediating intercellular signaling in EVs formation (Project 1-EV Biogenesis), the engineering of biologically active payloads (Project 2-EV Payloads), and identifying specific cell types that internalize EVs in the wound bed (Project 3-EV Uptake). Together, these Projects address the over-arching goals of creating therapeutic EVs with a systematic approach that is optimized for specific cell types based on an understanding of 1) How and where EVs are made?; 2) How EVs are loaded and whether they are biologically active ?; and 3) Which cells uptake EVs to promote durable tissue repair.