Skull marrow crosstalk with the central nervous system

白细胞可以抵御病原体；然而，这些细胞也是急性和慢性疾病的主角。 中枢神经系统(CNS)疾病。而稳定状态的大脑依赖于局部来源的先天 免疫细胞，如小胶质细胞，能够募集来自造血细胞的免疫细胞 器官。特别是，中性粒细胞和单核细胞等先天免疫细胞迁移到患病的大脑中。 这些细胞是由骨髓中的造血干细胞和祖细胞(HSPC)产生的。 炎症状况，包括脑缺血，会增加髓系细胞的产生，而髓系细胞 随后招募到缺血脑。同样，慢性炎症性中枢神经系统疾病可能导致 白细胞募集。新出现的数据表明，招募的白细胞追求与以下方面高度相关的功能 大脑的恢复和功能。目前的教条认为，在对全身刺激的反应中，造血细胞 骨髓均匀地将白细胞释放到体循环中，这些白细胞迁移到 损伤的大脑通过颈动脉和椎动脉。我们发现了连接的小血管通道 颅骨的骨髓和大脑的表面。这些20微米大小的通道穿过内颅骨皮质 包被内皮细胞，中性粒细胞和单核细胞经常出现。我们未公布的初步数据 证明这种白细胞在炎症条件下迁移增加。我们开发了成像工具， 包括活体内显微镜，以询问这些通道中的细胞流量。在这里，我们建议将 这一假设的可供选择的稳定状态下的白细胞迁移途径，作为衰老和 发展、缺血性中风后和高血压。我们将测试最重要的假设，即 血管通道是白细胞从颅骨骨髓到中枢神经系统炎症部位的一条“捷径”。因为它 目前尚不清楚头骨骨髓是否与椎骨中的骨髓功能同步， 骨盆和长骨，或者表现出地区性独特的特性，这可能是重要的，因为它的 在接近大脑的位置，我们将比较颅骨骨髓来源的白细胞与其他来源的细胞的功能。 造血部位处于稳态、高血压和脑缺血后。此应用程序将一个 拥有神经科学、血液学、免疫学、血管生物学和影像学专业知识的跨学科团队 研究可能连接造血性颅骨组织和硬脑膜、中枢神经系统的新型微血管 表面，可能还有实质。所获得的洞察力可能会为新的抗炎治疗提供参考 炎症性中枢神经系统疾病的治疗方法。

Leukocytes protect against pathogens; however, these cells are also protagonists of acute and chronic diseases of the central nervous system (CNS). While the steady-state brain relies on locally sourced innate immune cells such as microglia which enables recruitment of immune cells that arise from hematopoietic organs. In particular, innate immune cells such as neutrophils and monocytes migrate to the diseased brain. These cells are produced by hematopoietic stem and progenitor cells (HSPC) in the bone marrow. Inflammatory conditions, including brain ischemia, increase the production of myeloid cells, which are subsequently recruited to the ischemic brain. Similarly, chronic inflammatory CNS disorders may lead to leukocyte recruitment. Emerging data indicate that recruited leukocytes pursue functions with high relevance to brain recovery and function. The current dogma states that in response to systemic stimuli, hematopoietic marrow homogenously releases leukocytes into the systemic circulation and that these leukocytes migrate to the injured brain via the carotid and vertebral arteries. We discovered small vascularized channels that connect the skull bone marrow with the surface of the brain. These 20µm sized channels through the inner skull cortex are clad with endothelial cells and frequented by neutrophils and monocytes. Our unpublished preliminary data document that this leukocyte migration increases in inflammatory conditions. We developed imaging tools, including intravital microscopy, to interrogate cellular traffic in these channels. Here we propose to characterize this hypothetical alternative leukocyte migration route in the steady state, as a function of aging and development, after ischemic stroke and in hypertension. We will test the overarching hypothesis that small vascular channels serve as a "short cut" for leukocytes from skull marrow to sites of CNS inflammation. Since it is currently unknown whether the skull bone marrow functions in synchrony with the marrow in vertebrae, pelvis and long bones, or alternatively exhibits regionally unique properties that may be important due to its proximity to the brain, we will compare the function of skull marrow derived leukocytes to cells made in other hematopoietic sites in steady state, hypertension and after brain ischemia. This application unites an interdisciplinary team with expertise in neuroscience, hematology, immunology, vascular biology and imaging to investigate novel microvasculature that may connect the hematopoietic skull tissue with the dura, the CNS surface and possibly parenchyma. The gained insight may inform novel anti-inflammatory therapeutic approaches for the treatment of inflammatory CNS disorders.