Regulation of monocyte cell fate by blood vessels through Notch signaling and significance for vascular repair

血管损伤会引发炎症反应，以消除刺激物，启动修复和再生。这种反应涉及单核细胞和血管之间的相互作用，在生理和病理条件下，单核细胞和血管之间处于持续的串扰状态。单核细胞的一个亚群，称为巡逻或Ly6Clo单核细胞，通过沿着血管内皮细胞爬行来巡逻血管。巡逻单核细胞参与缺血后的组织修复，但也协调损伤后的内皮修复。然而，这些单核细胞的来源和调控在很大程度上仍不清楚，它们对损伤后内皮细胞恢复的意义也不完全清楚。在初步工作中，我们已经定义了调控这个单核细胞亚群起源的分子和细胞背景。综上所述，我们的结果表明，Notch信号调节常规(Ly6chi)单核细胞向Ly6Clo单核细胞的转化，从而调节稳定条件下单核细胞命运的特定发育步骤。这一过程由一群EC表达的Notch配体特异性地控制，这些EC在骨髓和脾中构成了不同的血管壁龛。因此，血管调节单核细胞转化，作为发育细胞命运调节的一种形式。我们现在打算定义控制Ly6Clo单核细胞发育的分子机制和血管生态位成分，并旨在分析它们在内皮损伤模型中的意义。具体地说，根据初步数据，我们假设Notch信号在巡逻单核细胞的发育过程中与TLR信号通路相互作用，并将在体外和体内测试这一机制。我们将在已建立的颈动脉内皮损伤后内皮修复模型中表征巡逻单核细胞的特殊血管功能和单核细胞Notch信号。我们将进一步确定血管龛的特征，测试脾在生理条件下对单核细胞的发育和巡逻功能的具体作用，以及脾龛功能在内皮损伤和修复中的相关性。最后，我们的目标是建立人类巡视单核细胞的体外培养系统，以期将其用于治疗目的。因此，我们建议研究决定单核细胞命运的机制，并阐明炎症和血管修复的基础。了解这一点对于设计有效的炎症性疾病治疗策略可能是至关重要的。

Injury of blood vessels triggers an inflammatory response intended to eliminate the inciting agent and initiate repair and regeneration. This response involves the interaction of monocytes and blood vessels, which are in constant crosstalk with each other under physiological and pathological conditions. A subpopulation of monocytes, known as patrolling or Ly6Clo monocytes, patrol blood vessels by crawling along the vascular endothelium. Patrolling monocytes are involved in tissue repair after ischemia, but also orchestrate endothelial repair after injury. However, the origin and regulation of these monocytes is still largely unknown, and their significance for endothelial recovery after injury incompletely understood. In preliminary work we have defined the molecular and cellular context that regulates the origin of this monocyte subset. Taken together, our results show that Notch signaling regulates conversion of conventional (Ly6Chi) monocytes into Ly6Clo monocytes, thereby regulating a specific developmental step in monocyte cell fate under steady-state conditions. This process is controlled specifically by a Notch ligand expressed by a population of EC that constitute distinct vascular niches in the bone marrow and spleen. Thus, blood vessels regulate monocyte conversion, as a form of developmental cell fate regulation.We now intend to define the molecular mechanism and vascular niche constituents that govern Ly6Clo monocyte development and aim to analyze their significance in models of endothelial injury. Specifically, based on preliminary data, we hypothesize that Notch signaling interacts with the TLR signaling pathway during the development of patrolling monocytes and will test this mechanism in vitro and in vivo. We will characterize the specific vascular function of patrolling monocytes and monocyte Notch signaling in established models of endothelial repair after carotid endothelial injury. We will further characterize the vascular niche and test the specific role of the spleen for the development and function of patrolling monocytes in physiological conditions, but also the relevance of the splenic niche function in endothelial injury and repair. Finally, we will aim to develop in vitro culture system for human patrolling monocytes with the intention to use them for treatment purposes.We propose therefore to study the mechanisms defining monocyte cell fate and elucidate fundamentals of inflammation and vascular repair. The knowledge of this might be crucial for the design of efficient treatment strategies in the therapy of inflammatory diseases.