Myeloid cell fate decisions in ischemic neovascularization: Regulation of monocyte and macrophage subsets by Notch signaling and functional significance for arteriogenesis.

缺血引起旨在引发血管修复和再生的炎症反应，但通常导致慢性炎症和死亡。单核细胞和巨噬细胞的异质性是先天免疫系统的标志，也是环境依赖性骨髓可塑性的范例。然而，谱系关系和调节单核细胞和巨噬细胞异质性的分子途径还不清楚。造血细胞命运决定和缺血性组织再生由Notch信号传导调节，其由激活不同Notch受体的各种Notch配体指定。我们自己的研究结果表明，Notch信号不仅影响单核细胞亚群的组成，还影响缺血中功能性巨噬细胞的极化，从而调节缺血性组织再生和慢性炎症之间的平衡。我们建议解决Notch信号如何调节单核细胞和巨噬细胞的命运和功能。我们将研究单核细胞和巨噬细胞亚群之间的谱系关系，并表征Notch信号传导的功能作用。具体来说，我们解决的假设，单核细胞亚群的影响，不同的Notch受体调节谱系转换和/或功能成熟。我们还将研究血管内皮细胞如何通过Notch配体调节单核细胞亚群和功能，以及脾脏是否为Notch信号传导提供了一个利基，从而有助于单核细胞教育。我们将进一步研究单核细胞亚群与缺血性巨噬细胞之间的谱系关系，全面表征单核细胞向巨噬细胞分化过程中激活的转录程序，并研究特异性Notch受体对巨噬细胞表型和功能的调节。这些实验有望确定调节骨髓可塑性和谱系关系的机制，加深我们对炎症调节的理解。这也可能确定参与缺血性组织再生的特定分子途径和细胞群，这可能使新的治疗方式成为可能。

Ischemia causes an inflammatory response intended to initate vascular repair and regeneration, but often leads to chronic inflammation and demise. Heterogeneity of monocytes and macrophages is a hallmark of the innate immune system and a paradigm for context-dependent myeloid plasticity. However, lineage-relationships and molecular pathways regulating monocyte and macrophage heterogeneity are not well understood. Hematopoietic cell fate decisions and ischemic tissue regeneration are regulated by Notch signaling, which is specified by various Notch ligands activating different Notch receptors. Our own results show that Notch signaling influences monocyte subset composition but also functional macrophage polarization in ischemia, which regulates a balance between ischemic tissue regeneration and chronic inflammation. We propose to address how Notch signaling regulates monocyte and macrophage cell fate and function. We will investigate the lineage relationships between monocyte and macrophage subsets and characterize the functional role of Notch signaling. Specifically, we address the hypothesis that monocyte subsets are influenced by different Notch receptors regulating lineage conversion and/or functional maturation. We will also study how the vascular endothelium regulates monocyte subsets and function through Notch ligands, and whether the spleen provides a niche for Notch signaling, thus contributing to monocyte education. We will further investigate the lineage relationships between monocyte subsets and ischemic macrophages, comprehensively characterize the trancriptional programm activated during monocyte-to-macrophage differentiation and study the regulation of macrophage phenotype and function by specific Notch receptors. These experiments are expected to identify mechanisms regulating myeloid plasticity and lineage relationships, deepening our understanding of the regulation of inflammation. This might also identify specific molecular pathways and cell populations involved in ischemic tissue regeneration, which might enable new therapeutic modalities.