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Leptomeninges, consisting of the pia mater and arachnoid, form a connective tissue investment and barrier enclosure of the brain. The exact nature of leptomeningeal cells has long been debated. In this study, we iden-tify five molecularly distinct fibroblast-like transcriptomes in cerebral leptomeninges; link them to anatomically distinct cell types of the pia, inner arachnoid, outer arachnoid barrier, and dural border layer; and contrast them to a sixth fibroblast-like transcriptome present in the choroid plexus and median eminence. Newly identified transcriptional markers enabled molecular characterization of cell types responsible for adherence of arach-noid layers to one another and for the arachnoid barrier. These markers also proved useful in identifying the molecular features of leptomeningeal development, injury, and repair that were preserved or changed after traumatic brain injury. Together, the findings highlight the value of identifying fibroblast transcriptional subsets and their cellular locations toward advancing the understanding of leptomeningeal physiology and pathology., De fyra första författarna delar förstaförfattarskapetDe tre sista författarna delar sistaförfattarskapet

Formation of the mouse cerebellum is initiated in the embryo and continues for a few weeks after birth. Double-mutant mice lacking platelet-derived growth factor C (PDGF-C) and that are heterozygous for platelet-derived growth factor receptor alpha (Pdgfc(-/-); Pdgfra(GFP/+)) develop cerebellar hypoplasia and malformation with loss of cerebellar lobes in the posterior vermis. This phenotype is similar to those observed in Foxc1 mutant mice and in a human neuroimaging pattern called Dandy Walker malformation. Pdgfc-Pdgfra mutant mice also display ependymal denudation in the fourth ventricle and gene expression changes in cerebellar meninges, which coincide with the first visible signs of cerebellar malformation. Here, we show that PDGF-C/PDGFR alpha signalling is a critical component in the network of molecular and cellular interactions that take place between the developing meninges and neural tissues, and which are required to build a fully functioning cerebellum.

Cerebrovascular disease is the third most common cause of death in developed countries, but our understanding of the cells that compose the cerebral vasculature is limited. Here, using vascular single-cell transcriptomics, we provide molecular definitions for the principal types of blood vascular and vessel-associated cells in the adult mouse brain. We uncover the transcriptional basis of the gradual phenotypic change (zonation) along the arteriovenous axis and reveal unexpected cell type differences: a seamless continuum for endothelial cells versus a punctuated continuum for mural cells. We also provide insight into pericyte organotypicity and define a population of perivascular fibroblast-like cells that are present on all vessel types except capillaries. Our work illustrates the power of single-cell transcriptomics to decode the higher organizational principles of a tissue and may provide the initial chapter in a molecular encyclopaedia of the mammalian vasculature.

Vascular diseases are major causes of death, yet our understanding of the cellular constituents of blood vessels, including how differences in their gene expression profiles create diversity in vascular structure and function, is limited. In this paper, we describe a single-cell RNA sequencing (scRNA-seq) dataset that defines vascular and vessel-associated cell types and subtypes in mouse brain and lung. The dataset contains 3,436 single cell transcriptomes from mouse brain, which formed 15 distinct clusters corresponding to cell (sub) types, and another 1,504 single cell transcriptomes from mouse lung, which formed 17 cell clusters. In order to allow user-friendly access to our data, we constructed a searchable database (http://betsholtzlab.org/VascularSingleCells/database.html). Our dataset constitutes a comprehensive molecular atlas of vascular and vessel-associated cell types in the mouse brain and lung, and as such provides a strong foundation for future studies of vascular development and diseases., De två första författarna delar förstaförfattarskapet.

Cells in the early neuroepithelium differentiate and give rise to all cells in the central nervous system (CNS). The ways from a multipotent CNS stem cell to specialized neurons and glia are not fully understood. Using immunohistochemistry we found that neuroepithelial cells express the platelet-derived growth factor receptor-alpha (PDGFR-alpha) in the neural plate at embryonic day 8.5 and onwards in the neural tube. The protein was polarized to ventricular endfeet. Furthermore, PDGFR-alpha expression was localized to cells undergoing early neuronal development. We also found PDGFR-alpha expression in developing granule cells in the postnatal cerebellum, in Purkinje cells in the adult cerebellum and on processes of developing dorsal root ganglion cells. Previous reports mainly describe PDGFR-alpha expression in oligodendrocyte precursors and glial cells. We believe, in line with a few previous reports, that the PDGFR-alpha in addition marks a pool of undifferentiated cells, which are able to differentiate into neurons.

Platelet-derived growth factor B (PDGFB) plays a crucial role in recuitment of PDGF-receptor b positive pericytes to blood vessels and the endothelium is an essential source of PDGFB in this process. PDGFB was originally isolated from platelets, which consitute a major reservoir of this growth factor. Under physiological conditions, platelets are not activated unless there is a wound, which then leads to rapid activation and degranulation of the platelet content. However, in the tumor microenvironment platelets are continuously activated, exposing tumors to the plethora of growth factors contained in platelet granules. In the current study we address the role of platelet-derived PDGFB in vascular function and pericyte recruitment in tumors by creating a platelet-specific knock-out of PDGFB. We find that mice with PDGFB-deficient platelets are viable and fertile. Furthermore, vascular function and pericyte recruitment to healthy vessels were unaffected by the lack of PDGFB in platelets. In contrast, tumor vascular function, as well as pericyte coverage, is significantly impaired in mice with PDGFB-deficient platelets. Moreover, lack of PDGFB in platelets leads to enhanced spontaneous liver metastasis in a model for pancreatic neuroendocrine carcinoma, further indicating that platelet-derived PDGFB contributes to maintain vascular integrity in the tumor microenvironment where extensive vascular remodeling is ongoing. With this finding we identify a previously unknown role for platelet-derived PDGFB.

Platelet-derived growth factor B (PDGFB) plays a crucial role in recuitment of PDGF-receptor b positive pericytes to blood vessels and the endothelium is an essential source of PDGFB in this process. PDGFB was originally isolated from platelets, which consitute a major reservoir of this growth factor. Under physiological conditions, platelets are not activated unless there is a wound, which then leads to rapid activation and degranulation of the platelet content. However, in the tumor microenvironment platelets are continuously activated, exposing tumors to the plethora of growth factors contained in platelet granules. In the current study we address the role of platelet-derived PDGFB in vascular function and pericyte recruitment in tumors by creating a platelet-specific knock-out of PDGFB. We find that mice with PDGFB-deficient platelets are viable and fertile. Furthermore, vascular function and pericyte recruitment to healthy vessels were unaffected by the lack of PDGFB in platelets. In contrast, tumor vascular function, as well as pericyte coverage, is significantly impaired in mice with PDGFB-deficient platelets. Moreover, lack of PDGFB in platelets leads to enhanced spontaneous liver metastasis in a model for pancreatic neuroendocrine carcinoma, further indicating that platelet-derived PDGFB contributes to maintain vascular integrity in the tumor microenvironment where extensive vascular remodeling is ongoing. With this finding we identify a previously unknown role for platelet-derived PDGFB.

Platelet-derived growth factor B (PDGFB) plays a crucial role in recuitment of PDGF-receptor b positive pericytes to blood vessels and the endothelium is an essential source of PDGFB in this process. PDGFB was originally isolated from platelets, which consitute a major reservoir of this growth factor. Under physiological conditions, platelets are not activated unless there is a wound, which then leads to rapid activation and degranulation of the platelet content. However, in the tumor microenvironment platelets are continuously activated, exposing tumors to the plethora of growth factors contained in platelet granules. In the current study we address the role of platelet-derived PDGFB in vascular function and pericyte recruitment in tumors by creating a platelet-specific knock-out of PDGFB. We find that mice with PDGFB-deficient platelets are viable and fertile. Furthermore, vascular function and pericyte recruitment to healthy vessels were unaffected by the lack of PDGFB in platelets. In contrast, tumor vascular function, as well as pericyte coverage, is significantly impaired in mice with PDGFB-deficient platelets. Moreover, lack of PDGFB in platelets leads to enhanced spontaneous liver metastasis in a model for pancreatic neuroendocrine carcinoma, further indicating that platelet-derived PDGFB contributes to maintain vascular integrity in the tumor microenvironment where extensive vascular remodeling is ongoing. With this finding we identify a previously unknown role for platelet-derived PDGFB.