SwePub - search: WFRF:(Andrae Johanna)

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1.	Andrae, Johanna, et al. (author) A 1.8kb GFAP-promoter fragment is active in specific regions of theembryonic CNS 2001 In: Mechanisms of Development. - 0925-4773 .- 1872-6356. ; 107:1-2, s. 181-5 Journal article (peer-reviewed)abstract The intermediate filament glial fibrillary acidic protein (GFAP) constitutes the major cytoskeletal protein in astrocytes (J. Neuroimmunol. 8 (1985) 203) and is traditionally referred to as a specific marker for astrocytes. To identify early glial precursors, we created GFAPpromoter-lacZ transgenic mice, using a 1.8kb 5' fragment of human GFAP. The expression of the transgene was first detected in the neuroepithelium at embryonic day 9.5. It was further found in the ventricular zone of the developing telencephalon, in the cerebellar primordium, trigeminal ganglia, and radial glia. Later, scattered beta-gal+ cells were seen in pons, brain stem and glia limitans. The results indicate that GFAP activity is regulated in a region-specific manner during central nervous system (CNS) development and that the gene is turned on in different cell types independently.
2.	Andrae, Johanna, et al. (author) A role for PDGF-C/PDGFR alpha signaling in the formation of the meningeal basement membranes surrounding the cerebral cortex 2016 In: Biology Open. - : The Company of Biologists. - 2046-6390. ; 5:4, s. 461-474 Journal article (peer-reviewed)abstract Platelet-derived growth factor-C (PDGF-C) is one of three known ligands for the tyrosine kinase receptor PDGFR alpha. Analysis of Pdgfc null mice has demonstrated roles for PDGF-C in palate closure and the formation of cerebral ventricles, but redundancy with other PDGFR alpha ligands might obscure additional functions. In search of further developmental roles for PDGF-C, we generated mice that were double mutants for Pdgfc(-/-) and Pdgfra(GFP/+). These mice display a range of severe phenotypes including spina bifida, lung emphysema, abnormal meninges and neuronal over-migration in the cerebral cortex. We focused our analysis on the central nervous system (CNS), where PDGF-C was identified as a critical factor for the formation of meninges and assembly of the glia limitans basement membrane. We also present expression data on Pdgfa, Pdgfc and Pdgfra in the cerebral cortex and microarray data on cerebral meninges.
3.	Andrae, Johanna, et al. (author) Analysis of Mice Lacking the Heparin-Binding Splice Isoform of Platelet-Derived Growth Factor A 2013 In: Molecular and Cellular Biology. - 0270-7306 .- 1098-5549. ; 33:20, s. 4030-4040 Journal article (peer-reviewed)abstract Platelet-derived growth factor A-chain (PDGF-A) exists in two evolutionarily conserved isoforms, PDGF-Along and PDGF-Ashort, generated by alternative RNA splicing. They differ by the presence (in PDGF-Along) or absence (in PDGF-Ashort) of a carboxyterminal heparin/heparan sulfate proteoglycan-binding motif. In mice, similar motifs present in other members of the PDGF and vascular endothelial growth factor (VEGF) families have been functionally analyzed in vivo, but the specific physiological importance of PDGF-A(long) has not been explored previously. Here, we analyzed the absolute and relative expression of the two PDGF-A splice isoforms during early postnatal organ development in the mouse and report on the generation of a Pdgfa allele (Pdgfa(Delta ex6) incapable of producing PDGF-A(long) due to a deletion of the exon 6 splice acceptor site. In situations of limiting PDGF-A signaling through PDGF receptor alpha (PDGFR alpha), or in mice lacking PDGF-C, homozygous carriers of Pdgfa(Delta ex6) showed abnormal development of the lung, intestine, and vertebral column, pinpointing developmental processes where PDGF-A(long) may play a physiological role.
4.	Andrae, Johanna, et al. (author) Characterization of Platelet-Derived Growth Factor-A Expression in Mouse Tissues Using a lacZ Knock-In Approach 2014 In: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 9:8, s. e105477- Journal article (peer-reviewed)abstract Expression of the platelet-derived growth factor A-chain gene (Pdgfa) occurs widely in the developing mouse, where it is mainly localized to various epithelial and neuronal structures. Until now, in situ mRNA hybridization (ISH) has been the only reliable method to identify Pdgfa expression in tissue sections or whole mount preparations. Validated protocols for in situ detection of PDGF-A protein by immunohistochemistry is lacking. In particular, this has hampered understanding of Pdgfa expression pattern in adult tissues, where ISH is technically challenging. Here, we report a gene targeted mouse Pdgfa allele, Pdgfa(ex4COIN), which is a combined conditional knockout and reporter allele. Cre-mediated inversion of the COIN cassette inactivates Pdgfa coding while simultaneously activating a beta-galactosidase (lacZ) reporter under endogenous Pdgfa transcription control. The generated Pdgfa(ex4COIN-INV-lacZ) allele can next be used to identify cells carrying a Pdgfa null allele, as well as to map endogenous Pdgfa expression. We evaluated the Pdgfa(ex4COIN-INV-lacZ) allele as a reporter for endogenous Pdgfa expression patterns in mouse embryos and adults. We conclude that the expression pattern of Pdgfa(ex4COIN-INV-lacZ) recapitulates known expression patterns of Pdgfa. We also report on novel embryonic and adult Pdgfa expression patterns in the mouse and discuss their implications for Pdgfa physiology.
5.	Andræ, Johanna (author) PDGF in cerebellar development and tumorigenesis 2001 Doctoral thesis (other academic/artistic)abstract Medulloblastoma is a highly malignant cerebellar childhood tumor. As in many other brain tumors, expression of platelet-derived growth factor (PDGF) and its receptors has been shown in medulloblastoma. To reveal the importance of this growth factor in cerebellar development and tumorigenesis, analyses were performed on human medulloblastoma cell lines and on tissue from normal mouse brain at different stages of development. The in vivo effect of a forced expression of PDGF-B in the cerebellar primordium was examined in transgenic mice. In the normal mouse embryo, we found PDGF receptor-α-positive cells in the early neuroepithelium and on neuronal precursors. In the postnatal cerebellum, cells in the external germinal layer and Purkinje cells expressed the receptor. In the medulloblastoma cells, expression of all the three PDGF isoforms and PDGF receptors was seen and correlated to neuronal differentiation. Endogenously activated, i.e. tyrosine phosphorylated, PDGF receptors were identified. To reveal the role of PDGF in normal cerebellar development, we established transgenic mice where a PDGF-B cDNA was introduced via homologous recombination into the engrailed-1 gene. Engrailed-1 is specifically expressed at the mid-/hindbrain boundary of the early neural tube, i.e. in an area from which the cerebellar primordium develops. The ectopic expression of PDGF-B caused a disturbance of cerebellar development. Midline fusion of the cerebellar primordium did not occur properly, which resulted in cerebellar dysplasia in the adult mouse.In a parallel study, the expression pattern of a glial fibrillary acidic protein (GFAP)-lacZ transgene was followed in the embryonic mouse central nervous system. It was shown that the human GFAP promoter was already active by embryonic day 9.5 and as development proceeded, expression occured in different, independent cell populations. Among these cell populations were the radial glial cells in the neocortex.
6.	Andrae, Johanna, et al. (author) PDGFR alpha signaling is required for alveolar development in the mouse lung 2017 In: Mechanisms of Development. - : ELSEVIER SCIENCE BV. - 0925-4773 .- 1872-6356. ; 145, s. S147-S147 Journal article (other academic/artistic)
7.	Andrae, Johanna, et al. (author) Platelet-derived growth factor-B and -C and active alpha-receptors in medulloblastoma cells. 2002 In: Biochemical and biophysical research communications. - 0006-291X .- 1090-2104. ; 296:3, s. 604-11 Journal article (peer-reviewed)abstract The malignant childhood brain tumor medulloblastoma belongs to the group of primitive neuroectodermal tumours (PNETs). Medulloblastomas are thought to arise from remnants of the transient external germinal layer in the cerebellum. Proliferation, differentiation, and motility of cells in the central nervous system are regulated by growth factors, e.g., platelet-derived growth factor (PDGF). Recently, it was shown that higher level of PDGF alpha-receptor expression is characteristic of metastatic medulloblastomas. We have investigated five medulloblastoma/PNET cell lines and found that the PDGF alpha-receptor is actively signalling in most of them, an activity most likely driven by endogenously produced PDGF-C. PDGF-C is normally present in cells of the developing external germinal layer and our results are consistent with the idea that medulloblastomas are derived from such cells undergoing early neuronal differentiation. Moreover, the expression of PDGF and its receptors was associated with neuronal characteristics, but not with high levels of c-myc expression in the medullablastoma cells.
8.	Andrae, Johanna, et al. (author) Platelet-derived growth factor receptor-alpha in ventricular zone cells and in developing neurons. 2001 In: Molecular and Cellular Neuroscience. - : Elsevier BV. - 1044-7431 .- 1095-9327. ; 17:6 Journal article (peer-reviewed)abstract 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.
9.	Dang, Thanh Chung, et al. (author) Powerful Homeostatic Control of Oligodendroglial Lineage by PDGFR alpha in Adult Brain 2019 In: Cell Reports. - : CELL PRESS. - 2211-1247. ; 27:4, s. 1073-1089 Journal article (peer-reviewed)abstract Oligodendrocyte progenitor cells (OPCs) are widely distributed cells of ramified morphology in adult brain that express PDGFR alpha and NG2. They retain mitotic activities in adulthood and contribute to oligodendrogenesis and myelin turnover; however, the regulatory mechanisms of their cell dynamics in adult brain largely remain unknown. Here, we found that global Pdgfra inactivation in adult mice rapidly led to elimination of OPCs due to synchronous maturation toward oligodendrocytes. Surprisingly, OPC densities were robustly reconstituted by the active expansion of Nestin(+) immature cells activated in meninges and brain parenchyma, as well as a few OPCs that escaped from Pdgfra inactivation. The multipotent immature cells were induced in the meninges of Pdgfra-inactivated mice, but not of control mice. Our findings revealed powerful homeostatic control of adult OPCs, engaging dual cellular sources of adult OPC formation. These properties of the adult oligodendrocyte lineage and the alternative OPC source may be exploited in regenerative medicine.
10.	De La Fuente, Alerie Guzman, et al. (author) Pericytes Stimulate Oligodendrocyte Progenitor Cell Differentiation during CNS Remyelination 2017 In: Cell Reports. - : Elsevier BV. - 2211-1247. ; 20:8, s. 1755-1764 Journal article (peer-reviewed)abstract The role of the neurovascular niche in CNS myelin regeneration is incompletely understood. Here, we show that, upon demyelination, CNS-resident pericytes (PCs) proliferate, and parenchymal non-vessel-associated PC-like cells (PLCs) rapidly develop. During remyelination, mature oligodendrocytes were found in close proximity to PCs. In Pdgfb(ret/ret) mice, which have reduced PC numbers, oligodendrocyte progenitor cell (OPC) differentiation was delayed, although remyelination proceeded to completion. PC-conditioned medium accelerated and enhanced OPC differentiation in vitro and increased the rate of remyelination in an ex vivo cerebellar slice model of demyelination. We identified Lama2 as a PC-derived factor that promotes OPC differentiation. Thus, the functional role of PCs is not restricted to vascular homeostasis but includes the modulation of adult CNS progenitor cells involved in regeneration.
11.	Gallini, Radiosa, et al. (author) Isoform-Specific Modulation of Inflammation Induced by Adenoviral Mediated Delivery of Platelet-Derived Growth Factors in the Adult Mouse Heart 2016 In: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 11:8 Journal article (peer-reviewed)abstract Platelet-derived growth factors (PDGFs) are key regulators of mesenchymal cells in vertebrate development. To what extent PDGFs also exert beneficial homeostatic or reparative roles in adult organs, as opposed to adverse fibrogenic responses in pathology, are unclear. PDGF signaling plays critical roles during heart development, during which forced overexpression of PDGFs induces detrimental cardiac fibrosis; other studies have implicated PDGF signaling in post-infarct myocardial repair. Different PDGFs may exert different effects mediated through the two PDGF receptors (PDGFR alpha and PDGFR beta) in different cell types. Here, we assessed responses induced by five known PDGF isoforms in the adult mouse heart in the context of adenovirus vector-mediated inflammation. Our results show that different PDGFs have different, in some cases even opposing, effects. Strikingly, whereas the major PDGFRa agonists (PDGF-A and -C) decreased the amount of scar tissue and increased the numbers of PDGFR alpha-positive fibroblasts, PDGFR beta agonists either induced large scars with extensive inflammation (PDGF-B) or dampened the adenovirusinduced inflammation and produced a small and dense scar (PDGF-D). These results provide evidence for PDGF isoform-specific inflammation-modulating functions that may have therapeutic implications. They also illustrate a surprising complexity in the PDGF-mediated pathophysiological responses.
12.	Gallini, Radiosa, et al. (author) PDGF-A and PDGF-B induces cardiac fibrosis in transgenic mice 2016 In: Experimental Cell Research. - : Elsevier BV. - 0014-4827 .- 1090-2422. ; 349:2, s. 282-290 Journal article (peer-reviewed)abstract Platelet-derived growth factors (PDGFs) and their receptors (PDGFRs) contribute to normal heart development. Deficient or abnormal expression of Pdgf and Pdgfr genes have a negative impact on cardiac development and function. The cellular effects of PDGFs in the hearts of Pdgf/Pdgfr mutants and the pathogenesis of the resulting abnormalities are poorly understood, but different PDGF isoforms induce varying effects. Here, we generated three new transgenic mouse types which complete a set of studies, where all different PDGF ligands have been expressed under the same heart specific alpha-myosin heavy chain promoter. Transgenic expression of the natural isoforms of Pdgfa and Pdgfb resulted in isoform specific fibrotic reactions and cardiac hypertrophy. Pdgfa overexpression resulted in a severe fibrotic reaction with up to 8-fold increase in cardiac size, leading to lethal cardiac failure within a few weeks after birth. In contrast, Pdgfb overexpression led to focal fibrosis and moderate cardiac hypertrophy. As PDGF-A and PDGF-B have different affinity for the two PDGF receptors, we analyzed the expression of the receptors and the histology of the fibrotic hearts. Our data suggest that the stronger fibrotic effect generated by Pdgfa overexpression was mediated by Pdgfrα in cardiac interstitial mesenchymal cells, i.e. the likely source of extracellular matrix depostion and fibrotic reaction. The apparent sensitivity of the heart to ectopic PDGFRα agonists supports a role for endogenous PDGFRα agonists in the pathogenesis of cardiac fibrosis. © 2016 The Authors
13.	Gillnäs, Sara, et al. (author) Severe cerebellar malformations in mutant mice demonstrate a role for PDGF-C/PDGFR alpha signalling in cerebellar development 2022 In: BIOLOGY OPEN. - : COMPANY BIOLOGISTS LTD. - 2046-6390. ; 11:8 Journal article (peer-reviewed)abstract 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.
14.	Gouveia, Leonor, 1990-, et al. (author) Exploring the effect of PDGF-A deletion in the adult lung: implications in homeostasis and injury Other publication (other academic/artistic)
15.	Gouveia, Leonor, et al. (author) Expression analysis of platelet-derived growth factor receptor alpha and its ligands in the developing mouse lung 2017 In: Physiological Reports. - : WILEY. - 2051-817X. ; 5:6 Journal article (peer-reviewed)abstract Activation of the platelet-derived growth factor receptor-a (PDGFRa) signaling pathway is critically important during lung alveogenesis, the process in lung development during which alveoli are formed from the terminal alveolar sacs. Several studies have aimed to characterize the expression patterns of PDGFRa and its two ligands (PDGF-A and -C) in the lung, but published analyses have been limited to embryonic and/or perinatal time points, and no attempts have been made to characterize both receptor and ligand expression simultaneously. In this study, we present a detailed map of the expression patterns of PDGFRa, PDGF-A and PDGF-C during the entire period of lung development, that is, from early embryogenesis until adulthood. Three different reporter mice were analyzed (Pdgfa ex4-COIN-INV-lacZ, Pdgfc tm1Nagy, and Pdgfra tm11(EGFP) Sor), in which either lacZ or H2B-GFP were expressed under the respective promoter in gene-targeted alleles. A spatiotemporal dynamic expression was identified for both ligands and receptor. PDGF-A and PDGF-C were located to distinct populations of epithelial and smooth muscle cells, whereas PDGFRa expression was located to different mesenchymal cell populations. The detailed characterization of gene expression provides a comprehensive map of PDGFRa signaling in lung cells, opening up for a better understanding of the role of PDGF signaling during lung development.
16.	Gouveia, Leonor, et al. (author) PDGF-A signaling is required for secondary alveolar septation and controls epithelial proliferation in the developing lung 2018 In: Development. - : The Company of Biologists. - 0950-1991 .- 1477-9129. ; 145:7 Journal article (peer-reviewed)abstract Platelet-derived growth factor A (PDGF-A) signaling through PDGF receptor a is essential for alveogenesis. Previous studies have shown that Pdgfa(-/-) mouse lungs have enlarged alveolar airspace with absence of secondary septation, both distinctive features of bronchopulmonary dysplasia. To study how PDGF-A signaling is involved in alveogenesis, we generated lung-specific Pdgfa knockout mice (Pdgfa(fl/-); Spc-cre) and characterized their phenotype postnatally. Histological differences between mutant mice and littermate controls were visible after the onset of alveogenesis and maintained until adulthood. Additionally, we generated Pdgfa(fl/-); Spc-cre; Pdgfra(GFP/+) mice in which Pdgfra(+) cells exhibit nuclear GFP expression. In the absence of PDGF-A, the number of Pdgfra(GFP+) cells was significantly decreased. In addition, proliferation of Pdgfra(GFP+) cells was reduced. During alveogenesis, Pdgfra(GFP+) myofibroblasts failed to form the alpha-smooth muscle actin rings necessary for alveolar secondary septation. These results indicate that PDGF-A signaling is involved in myofibroblast proliferation and migration. In addition, we show an increase in both the number and proliferation of alveolar type II cells in Pdgfa(fl/-); Spc-cre lungs, suggesting that the increased alveolar airspace is not caused solely by deficient myofibroblast function.
17.	Gouveia, Leonor, 1990- (author) The role of PDGF-A in lung development, injury and repair 2018 Doctoral thesis (other academic/artistic)abstract The developmental processes that take place during embryogenesis depend on a great number of proteins that are important for cell-to-cell communication. Platelet-derived growth factors are known to be important for epithelial-mesenchymal interactions during development and organogenesis. However, many details are still lacking regarding organ-specific PDGF expression patterns and detailed cellular functions. This thesis aims to better describe the contribution of PDGF-A signaling to lung developmental and injury processes.To study the cell-specific expression patterns of PDGF-A we generated a reporter mouse that show LacZ expression in all PDGF-A positive cells. This mouse model was used to characterize PDGF-A expression in embryonic and adult mouse tissues (paper I).With the use of three different reporter mice, we described the cell type specific expression patterns of PDGF-A, PDGF-C and PDGFRα in mouse lungs, from embryonic day 10.5 (E10.5) when development is initiated, until adulthood (Postnatal day 60) when the lung is fully mature (paper II).A lung-specific Pdgfa knockout mouse was generated and the impact of the deletion was studied during lung development and adulthood. Mice lacking Pdgfa expression in the lung survived until adulthood but exhibited abnormal alveolar development. This phenotype was caused by the inability of myofibroblasts to assemble alpha smooth muscle actin ring around the forming alveoli (paper III).To investigate if PDGF-A is involved in the injury response mechanisms of the adult lung, we generated inducible lung-specific Pdgfa knockout mice. In homeostasis, adult Pdgfa deletion did not result in any apparent phenotype, whereas after hyperoxia-induced lung injury, preliminary data show that mutant mice exhibit substantially more alveolar damage and immune cell infiltration (paper IV).In conclusion, this thesis reports novel insights into the expression and role of PDGF-A and PDGFRα for the lung, both in development and adulthood.
18.	Gouveia, Maria Leonor Seguardo, et al. (author) Lung developmental arrest caused by PDGF-A deletion : consequences for the adult mouse lung 2020 In: American Journal of Physiology - Lung cellular and Molecular Physiology. - : AMER PHYSIOLOGICAL SOC. - 1040-0605 .- 1522-1504. ; 318:4, s. L831-L843 Journal article (peer-reviewed)abstract PDGF-A is a key contributor to lung development in mice. Its expression is needed for secondary septation of the alveoli and deletion of the gene leads to abnormally enlarged alveolar air spaces in mice. In humans, the same phenotype is the hallmark of bronchopulmonary dysplasia (BPD), a disease that affects premature babies and may have long lasting consequences in adulthood. So far, the knowledge regarding adult effects of developmental arrest in the lung is limited. This is attributable to few follow-up studies of BPD survivors and lack of good experimental models that could help predict the outcomes of this early age disease for the adult individual. In this study, we used the constitutive lung-specific Pdgfa deletion mouse model to analyze the consequences of developmental lung defects in adult mice. We assessed lung morphology, physiology, cellular content, ECM composition and proteomics data in mature mice, that perinatally exhibited lungs with a BPD-like morphology. Histological and physiological analyses both revealed that enlarged alveolar air spaces remained until adulthood, resulting in higher lung compliance and higher respiratory volume in knockout mice. Still, no or only small differences were seen in cellular, ECM and protein content when comparing knockout and control mice. Taken together, our results indicate that Pdgfa deletion-induced lung developmental arrest has consequences for the adult lung at the morphological and functional level. In addition, these mice can reach adulthood with a BPD-like phenotype, which makes them a robust model to further investigate the pathophysiological progression of the disease and test putative regenerative therapies.
19.	Guzman, A., et al. (author) Pericytes promote the generation of oligodendrocytes during remyelination 2017 In: Glia. - : Wiley. - 0894-1491 .- 1098-1136. ; 65:S1, s. E541-E542 Journal article (other academic/artistic)
20.	He, Liqun, et al. (author) Single-cell RNA sequencing of mouse brain and lung vascular and vessel-associated cell types 2018 In: Scientific Data. - : NATURE PUBLISHING GROUP. - 2052-4463. ; 5 Journal article (peer-reviewed)abstract 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.
21.	Hede, Sanna-Maria, et al. (author) GFAP promoter driven transgenic expression of PDGFB in the mouse brain leads to glioblastoma in a Trp53 null background 2009 In: Glia. - : Wiley. - 0894-1491 .- 1098-1136. ; 57:11, s. 1143-1153 Journal article (peer-reviewed)abstract Glioblastomas are the most common and malignant astrocytic brain tumors in human adults. The tumor suppressor gene TP53 is commonly mutated and/or lost in astrocytic brain tumors and the TP53 alterations are often found in combination with excessive growth factor signaling via PDGF/PDGFRalpha. Here, we have generated transgenic mice over-expressing human PDGFB in brain, under control of the human GFAP promoter. These mice showed no phenotype, but on a Trp53 null background a majority of them developed brain tumors. This occurred at 2-6 months of age and tumors displayed human glioblastoma-like features with integrated development of Pdgfralpha+ tumor cells and Pdgfrbeta+/Nestin+ vasculature. The transgene was expressed in subependymal astrocytic cells, in glia limitans, and in astrocytes throughout the brain substance, and subsequently, microscopic tumor lesions were initiated equally in all these areas. With tumor size, there was an increase in Nestin positivity and variability in lineage markers. These results indicate an unexpected plasticity of all astrocytic cells in the adult brain, not only of SVZ cells. The results also indicate a contribution of widely distributed Pdgfralpha+ precursor cells in the tumorigenic process.
22.	Kuppe, Christoph, et al. (author) Inverse correlation between vascular endothelial growth factor back-filtration and capillary filtration pressures 2018 In: Nephrology, Dialysis and Transplantation. - : OXFORD UNIV PRESS. - 0931-0509 .- 1460-2385. ; 33:9, s. 1514-1525 Journal article (peer-reviewed)abstract Background: Vascular endothelial growth factor A (VEGF) is an essential growth factor during glomerular development and postnatal homeostasis. VEGF is secreted in high amounts by podocytes into the primary urine, back-filtered across the glomerular capillary wall to act on endothelial cells. So far it has been assumed that VEGF back-filtration is driven at a constant rate exclusively by diffusion.Methods: In the present work, glomerular VEGF back-filtration was investigated in vivo using a novel extended model based on endothelial fenestrations as surrogate marker for local VEGF concentrations. Single nephron glomerular filtration rate (SNGFR) and/or local filtration flux were manipulated by partial renal mass ablation, tubular ablation, and in transgenic mouse models of systemic or podocytic VEGF overexpression or reduction.Results: Our study shows positive correlations between VEGF back-filtration and SNGFR as well as effective filtration rate under physiological conditions along individual glomerular capillaries in rodents and humans.Conclusion: Our results suggest that an additional force drives VEGF back-filtration, potentially regulated by SNGFR.
23.	Lange, S., et al. (author) CNS-pericytes promote oligodendrocyte fate decision and differentiation contributing to myelin development and repair 2015 In: Glia. - 0894-1491 .- 1098-1136. ; 63:S1, s. E289-E290 Journal article (other academic/artistic)
24.	Liu, Jianping, et al. (author) A human cell type similar to murine central nervous system perivascular fibroblasts 2021 In: Experimental Cell Research. - : Elsevier. - 0014-4827 .- 1090-2422. ; 402:2 Journal article (peer-reviewed)abstract The brain vasculature has several specific features, one of them being the blood-brain barrier (BBB), which supports and protects the brain by allowing for the passage of oxygen and nutrients, while at the same time preventing passage of pathogens and toxins. The BBB also prevents efficient delivery of drugs to the brain, e.g. for treatment of brain tumors. In the murine brain, perivascular fibroblasts were recently identified as a novel potential constituent of the BBB. Here we present the existence of human cells that could be the equivalent to the murine brain perivascular fibroblasts. Using RNA sequencing, we show a similar transcriptomic profile of cultured human brain cells and murine perivascular fibroblasts. These data open up a window for new hypotheses on cell types involved in human CNS diseases.
25.	Løvvik, Tone S., et al. (author) Use of metformin to treat pregnant women with polycystic ovary syndrome (PregMet2) : a randomised, double-blind, placebo-controlled trial 2019 In: The Lancet Diabetes and Endocrinology. - : Elsevier. - 2213-8587 .- 2213-8595. ; 7:4, s. 256-266 Journal article (peer-reviewed)abstract Background: Women with polycystic ovary syndrome (PCOS) have an increased risk of pregnancy complications. Epi-analysis of two previous randomised controlled trials that compared metformin with placebo during pregnancy in women with PCOS showed a significant reduction in late miscarriages and preterm births in the metformin group. The aim of this third randomised trial (PregMet2) was to test the hypothesis that metformin prevents late miscarriage and preterm birth in women with PCOS.Methods: PregMet2 was a randomised, placebo-controlled, double-blind, multicentre trial done at 14 hospitals in Norway, Sweden, and Iceland. Singleton pregnant women with PCOS aged 18-45 years were eligible for inclusion. After receiving information about the study at their first antenatal visit or from the internet, women signed up individually to participate in the study. Participants were randomly assigned (1: 1) to receive metformin or placebo by computer-generated random numbers. Randomisation was in blocks of ten for each country and centre; the first block had a random size between one and ten to assure masking. Participants were assigned to receive oral metformin 500 mg twice daily or placebo during the first week of treatment, which increased to 1000 mg twice daily or placebo from week 2 until delivery. Placebo tablets and metformin tablets were identical and participants and study personnel were masked to treatment allocation. The primary outcome was the composite incidence of late miscarriage (between week 13 and week 22 and 6 days) and preterm birth (between week 23 and week 36 and 6 days), analysed in the intention-to-treat population. Secondary endpoints included the incidence of gestational diabetes, preeclampsia, pregnancy-induced hypertension, and admission of the neonate to the neonatal intensive care unit. We also did a post-hoc individual participant data analysis of pregnancy outcomes, pooling data from the two previous trials with the present study. The study was registered with ClinicalTrials. gov, number NCT01587378, and EudraCT, number 2011-002203-15.Findings: The study took place between Oct 19, 2012, and Sept 1, 2017. We randomly assigned 487 women to metformin (n=244) or placebo (n=243). In the intention-to-treat analysis, our composite primary outcome of late miscarriage and preterm birth occurred in 12 (5%) of 238 women in the metformin group and 23 (10%) of 240 women in the placebo group (odds ratio [OR] 0.50, 95% CI 0.22- 1.08; p = 0.08). We found no significant differences for our secondary endpoints, including incidence of gestational diabetes (60 [25%] of 238 women in the metformin group vs 57 [24%] of 240 women in the placebo group; OR 1.09, 95% CI 0.69-1.66; p=0.75). We noted no substantial between-group differences in serious adverse events in either mothers or offspring, and no serious adverse events were considered drug-related by principal investigators. In the post-hoc pooled analysis of individual participant data from the present trial and two previous trials, 18 (5%) of 397 women had late miscarriage or preterm delivery in the metformin group ]compared with 40 (10%) of 399 women in the placebo group (OR 0.43, 95% CI 0.23-0.79; p=0.004).Interpretation: In pregnant women with PCOS, metformin treatment from the late first trimester until delivery might reduce the risk of late miscarriage and preterm birth, but does not prevent gestational diabetes.
26.	Mapunda, Josephine A., et al. (author) VE-cadherin in arachnoid and pia mater cells serves as a suitable landmark for in vivo imaging of CNS immune surveillance and inflammation 2023 In: Nature Communications. - : Springer Nature. - 2041-1723. ; 14:1 Journal article (peer-reviewed)abstract Meninges cover the surface of the brain and spinal cord and contribute to protection and immune surveillance of the central nervous system (CNS). How the meningeal layers establish CNS compartments with different accessibility to immune cells and immune mediators is, however, not well understood. Here, using 2-photon imaging in female transgenic reporter mice, we describe VE-cadherin at intercellular junctions of arachnoid and pia mater cells that form the leptomeninges and border the subarachnoid space (SAS) filled with cerebrospinal fluid (CSF). VE-cadherin expression also marked a layer of Prox1+ cells located within the arachnoid beneath and separate from E-cadherin+ arachnoid barrier cells. In vivo imaging of the spinal cord and brain in female VE-cadherin-GFP reporter mice allowed for direct observation of accessibility of CSF derived tracers and T cells into the SAS bordered by the arachnoid and pia mater during health and neuroinflammation, and detection of volume changes of the SAS during CNS pathology. Together, the findings identified VE-cadherin as an informative landmark for in vivo imaging of the leptomeninges that can be used to visualize the borders of the SAS and thus potential barrier properties of the leptomeninges in controlling access of immune mediators and immune cells into the CNS during health and neuroinflammation. How the leptomeninges establish CNS compartments with different accessibility to immune cells and immune mediators remains unknown. Here, the authors show junctional localization of VE-cadherin in arachnoid and pia mater cells, which allows to visualize potential barrier properties of the leptomeninges in vivo.
27.	Medrihan, Lucian, et al. (author) Neurobeachin, a protein implicated in membrane protein traffic and autism, is required for the formation and functioning of central synapses 2009 In: Journal of Physiology. - : Wiley. - 0022-3751 .- 1469-7793. ; 587:21, s. 5095-5106 Journal article (peer-reviewed)abstract The development of neuronal networks in the brain requires the differentiation of functional synapses. Neurobeachin (Nbea) was identified as a putative regulator of membrane protein trafficking associated with tubulovesicular endomembranes and postsynaptic plasma membranes. Nbea is essential for evoked transmission at neuromuscular junctions, but its role in the central nervous system has not been characterized. Here, we have studied central synapses of a newly generated gene-trap knockout (KO) mouse line at embryonic day 18, because null-mutant mice are paralysed and die perinatally. Although the overall brain architecture was normal, we identified major abnormalities of synaptic function in mutant animals. In acute slices from the brainstem, both spontaneous excitatory and inhibitory postsynaptic currents were clearly reduced and failure rates of evoked inhibitory responses were markedly increased. In addition, the frequency of miniature excitatory and both the frequency and amplitudes of miniature inhibitory postsynaptic currents were severely diminished in KO mice, indicating a perturbation of both action potential-dependent and -independent transmitter release. Moreover, Nbea appears to be important for the formation and composition of central synapses because the area density of mature asymmetric contacts in the fetal brainstem was reduced to 30% of wild-type levels, and the expression levels of a subset of synaptic marker proteins were smaller than in littermate controls. Our data demonstrate for the first time a function of Nbea at central synapses that may be based on its presumed role in targeting membrane proteins to synaptic contacts, and are consistent with the 'excitatory-inhibitory imbalance' model of autism where Nbea gene rearrangements have been detected in some patients.
28.	Nguyen, Quang Linh, et al. (author) Vascular PDGFR-alpha protects against BBB dysfunction after stroke in mice 2021 In: Angiogenesis. - : Springer. - 0969-6970 .- 1573-7209. ; 24, s. 35-46 Journal article (peer-reviewed)abstract Blood-brain barrier (BBB) dysfunction underlies the pathogenesis of many neurological diseases. Platelet-derived growth factor receptor-alpha (PDGFR alpha) induces hemorrhagic transformation (HT) downstream of tissue plasminogen activator in thrombolytic therapy of acute stroke. Thus, PDGFs are attractive therapeutic targets for BBB dysfunction. In the present study, we examined the role of PDGF signaling in the process of tissue remodeling after middle cerebral arterial occlusion (MCAO) in mice. Firstly, we found that imatinib increased lesion size after permanent MCAO in wild-type mice. Moreover, imatinib-induced HT only when administrated in the subacute phase of MCAO, but not in the acute phase. Secondly, we generated genetically mutated mice (C-KO mice) that showed decreased expression of perivascular PDGFR alpha. Additionally, transient MCAO experiments were performed in these mice. We found that the ischemic lesion size was not affected; however, the recruitment of PDGFR alpha/type I collagen-expressing perivascular cells was significantly downregulated, and HT and IgG leakage was augmented only in the subacute phase of stroke in C-KO mice. In both experiments, we found that the expression of tight junction proteins and PDGFR beta-expressing pericyte coverage was not significantly affected in imatinib-treated mice and in C-KO mice. The specific implication of PDGFR alpha signaling was suggestive of protective effects against BBB dysfunction during the subacute phase of stroke. Vascular TGF-beta 1 expression was downregulated in both imatinib-treated and C-KO mice, along with sustained levels of MMP9. Therefore, PDGFR alpha effects may be mediated by TGF-beta 1 which exerts potent protective effects in the BBB.
29.	Pietilä, Riikka, et al. (author) Molecular anatomy of adult mouse leptomeninges 2023 In: Neuron. - : Elsevier. - 0896-6273 .- 1097-4199. ; 111:23 Journal article (peer-reviewed)abstract 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.
30.	Rivera-Gonzalez, Guillermo C., et al. (author) Skin Adipocyte Stem Cell Self-Renewal Is Regulated by a PDGFA/AKT-Signaling Axis 2016 In: Cell Stem Cell. - : Elsevier BV. - 1934-5909 .- 1875-9777. ; 19:6, s. 738-751 Journal article (peer-reviewed)abstract Tissue growth and maintenance requires stem cell populations that self-renew, proliferate, and differentiate. Maintenance of white adipose tissue (WAT) requires the proliferation and differentiation of adipocyte stem cells (ASCs) to form postmitotic, lipid-filled mature adipocytes. Here we use the dynamic adipogenic program that occurs during hair growth to uncover an unrecognized regulator of ASC self-renewal and proliferation, PDGFA, which activates AKT signaling to drive and maintain the adipogenic program in the skin. Pdgfa expression is reduced in aged ASCs and is required for ASC proliferation and maintenance in the dermis, but not in other WATs. Our molecular and genetic studies uncover PI3K/AKT2 as a direct PDGFA target that is activated in ASCs during WAT hyperplasia and is functionally required for dermal ASC proliferation. Our data therefore reveal active mechanisms that regulate ASC self-renewal in the skin and show that distinct regulatory mechanisms operate in different WAT depots.
31.	Vanlandewijck, Michael, et al. (author) A molecular atlas of cell types and zonation in the brain vasculature 2018 In: Nature. - : NATURE PUBLISHING GROUP. - 0028-0836 .- 1476-4687. ; 554:7693, s. 475-480 Journal article (peer-reviewed)abstract 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.
32.	Yanyu, Zhang, et al. (author) Platelet-specific ablation of PDGFB impairs vascular function and pericyte recruitment in tumors and promotes metastasis Other publication (other academic/artistic)abstract 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.
33.	Zhang, Yanyu, et al. (author) Platelet-Specific PDGFB Ablation Impairs Tumor Vessel Integrity and Promotes Metastasis 2020 In: Cancer Research. - : American Association for Cancer Research (AACR). - 0008-5472 .- 1538-7445. ; 80:16, s. 3345-3358 Journal article (peer-reviewed)abstract Platelet-derived growth factor B (PDGFB) plays a crucial role in recruitment of PDGF receptor b-positive pericytes to blood vessels. The endothelium is an essential source of PDGFB in this process. Platelets constitute a major reservoir of PDGFB and are continuously activated in the tumor microenvironment, exposing tumors to the plethora of growth factors contained in platelet granules. Here, we show that tumor vascular function, as well as pericyte coverage is significantly impaired in mice with conditional knockout of PDGFB in platelets. A lack of PDGFB in platelets led to enhanced hypoxia and epithelial-to-mesenchymal transition in the primary tumors, elevated levels of circulating tumor cells, and increased spontaneous metastasis to the liver or lungs in two mouse models. These findings establish a previously unknown role for platelet-derived PDGFB, whereby it promotes and maintains vascular integrity in the tumor microenvironment by contributing to the recruitment of pericytes. Significance: Conditional knockout of PDGFB in platelets demonstrates its previously unknown role in the maintenance of tumor vascular integrity and host protection against metastasis.

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