The study of neuro-vascular interactions in the central nervous system

National Heart, Lung, And Blood Institute

Investigators

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Abstract

1) Developmental origin of CNS vascular cells. Mesoderm differentiates into brain endothelial cells and accessory pericytes: the quail-chicken chimera and labeling system demonstrated that the cephalic paraxial mesoderm has an angiogenic potential and contributes to the head and neck vasculature (Couly et al. Mech Dev 1995). Recent Cre-loxP-driven lineage tracing system has demonstrated heterogeneous origins of brain vascular cells from distinct populations, but brain vascular cells derived via a classical pathway of mesodermal differentiation into endothelial cells and pericytes remain to be investigated. With a combination of the published single cell RNA-sequence data set and whole-mount immunohistochemical and in situ hybridization analysis, we have identified a unique expression of hepatic leukemia factor (Hlf), the proline and acid rich basic region leucine zipper (Par-bZip) transcription factor, in the cephalic paraxial mesenchyme. Our lineage-tracing studies demonstrate that Hlf-expressing cephalic paraxial mesenchymal cells contribute to endothelial cells and pericytes in the developing brain vasculature (Koui et al. Biol Open 2022). Given that a recent report showed that the majority of lymphatic endothelial cells are derived from the paraxial mesoderm but not the lateral mesoderm (Stone and Stainier, Dev Cell 2019), it is interesting to examine how the cephalic paraxial mesenchymal cell-derived brain endothelial cells lose the lymphatic differentiation capability to develop the lymphatic avascular environment in the CNS parenchyma. 2) CNS blood and lymphatic vessel development. Our extensive immunohistochemical studies have clearly demonstrated that no lymphatic vasculature is found in the brain and spinal cord parenchyma, while lymphatic vessels form in the dura mater, the outermost of the three meningeal membranes that envelop the CNS (Izen et al. Dev Dyn 2018). We have also found that the Prox1-/LYVE1+ individual cells are distributed in the pial layer at an early developmental stage. Of interest, LYVE-1+ cells with macrophage-like morphology, called brain mural lymphatic endothelial cells, were reported on the surface of the zebrafish brain. Our lineage tracing studies show that the pial LYVE1+ cells are meningeal perivascular macrophages, but not lymphatic endothelial cells, suggesting that unlike zebrafish brain, no lymphatic endothelial cells or progenitors develop in close proximity to the CNS parenchyma. Moreover, our further studies show that LYVE-1+ macrophages control mitosis of radial glia cell (RGC), the primary source of cortical neurons in early brain development through their endfeet on the meninx, in an IGF1-Akt signaling-dependent manner (Liu, Sato, et al. Manuscript in preparation for resubmission). These data clearly highlight an essential developmental role for the pial macrophage-RGC interaction during cortical development. 3) A potential molecular link between BBB integrity and lymphatic avascularity The majority of lymphatic endothelial cells are produced by trans-differentiation from venous endothelium, when a subpopulation of venous endothelial cells expressing the key transcription factor Prox1 is specialized into lymphatic endothelial cells. Based on our observations that 1) brain endothelial cells do not express Prox1 and 2) brain endothelial cells do not differentiate into lymphatic endothelial cells in culture, we hypothesize that neural progenitor-derived signals (e.g. Wnt7a/b) induce CNS endothelial cell characteristics but suppress lymphatic endothelial cell differentiation potential. Indeed, ectopic Prox1 expression in CNS endothelial cells leads to BBB breakdown and hemorrhage, suggesting that Prox1 repression in the CNS ECs links between the BBB integrity and lymphatic avascularity (Gonzalez Hernandez et al. Manuscript in preparation). We are currently investigating the transcriptional regulation of Prox1 repression in CNS endothelial cells.