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| 3. |
- Fruttiger, M, et al.
(författare)
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Defective oligodendrocyte development and severe hypomyelination in PDGF-A knockout mice.
- 1999
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Ingår i: Development. - 0950-1991. ; 126:3, s. 457-67
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Tidskriftsartikel (refereegranskat)abstract
- There is a class of oligodendrocyte progenitors, called O-2A progenitors, that is characterized by expression of platelet-derived growth factor alpha-receptors (PDGFRalpha). It is not known whether all oligodendrocytes are derived from these PDGFRalpha-progenitors or whether a subset(s) of oligodendrocytes develops from a different, PDGFR alpha-negative lineage(s). We investigated the relationship between PDGF and oligodendrogenesis by examining mice that lack either PDGF-A or PDGF-B. PDGF-A null mice had many fewer PDGFR alpha-progenitors than either wild-type or PDGF-B null mice, demonstrating that proliferation of these cells relies heavily (though not exclusively) on PDGF-AA homodimers. PDGF-A-deficient mice also had reduced numbers of oligodendrocytes and a dysmyelinating phenotype (tremor). Not all parts of the central nervous system (CNS) were equally affected in the knockout. For example, there were profound reductions in the numbers of PDGFR alpha-progenitors and oligodendrocytes in the spinal cord and cerebellum, but less severe reductions of both cell types in the medulla. This correlation suggests a close link between PDGFRalpha-progenitors and oligodendrogenesis in most or all parts of the CNS. We also provide evidence that myelin proteolipid protein (PLP/DM-20)-positive cells in the late embryonic brainstem are non-dividing cells, presumably immature oligodendrocytes, and not proliferating precursors.
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| 4. |
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| 5. |
- Liu, Peidi, 1986, et al.
(författare)
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Transcriptomic and Proteomic Profiling Provides Insight into Mesangial Cell Function in IgA Nephropathy
- 2017
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Ingår i: Journal of the American Society of Nephrology. - : Ovid Technologies (Wolters Kluwer Health). - 1046-6673 .- 1533-3450. ; 28:10, s. 2961-2972
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Tidskriftsartikel (refereegranskat)abstract
- IgA nephropathy (IgAN), the most common GN worldwide, is characterized by circulating galactose-deficient IgA (gd-IgA) that forms immune complexes. The immune complexes are deposited in the glomerular mesangium, leading to inflammation and loss of renal function, but the complete pathophysiology of the disease is not understood. Using an integrated global transcriptomic and proteomic profiling approach, we investigated the role of the mesangium in the onset and progression of IgAN. Global gene expression was investigated by microarray analysis of the glomerular compartment of renal biopsy specimens from patients with IgAN (n=19) and controls (n=22). Using curated glomerular cell type specific genes from the published literature, we found differential expression of a much higher percentage of mesangial cell positive standard genes than podocyte-positive standard genes in IgAN. Principal coordinate analysis of expression data revealed clear separation of patient and control samples on the basis of mesangial but not podocyte cell positive standard genes. Additionally, patient clinical parameters (serum creatinine values and eGFRs) significantly correlated with Z scores derived from the expression profile of mesangial cell positive standard genes. Among patients grouped according to Oxford MEST score, patients with segmental glomerulosclerosis had a significantly higher mesangial cell positive standard gene Z score than patients without segmental glomerulosclerosis. By investigating mesangial cell proteomics and glomerular transcriptomics, we identified 22 common pathways induced in mesangial cells by gd-IgA, most of which mediate inflammation. The genes, proteins, and corresponding pathways identified provide novel insights into the pathophysiologic mechanisms leading to IgAN.
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| 7. |
- Pang, M-F, et al.
(författare)
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TGF-beta 1-induced EMT promotes targeted migration of breast cancer cells through the lymphatic system by the activation of CCR7/CCL21-mediated chemotaxis
- 2016
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Ingår i: Oncogene. - : Nature Publishing Group. - 0950-9232 .- 1476-5594. ; 35:6, s. 748-760
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Tidskriftsartikel (refereegranskat)abstract
- Tumor cells frequently disseminate through the lymphatic system during metastatic spread of breast cancer and many other types of cancer. Yet it is not clear how tumor cells make their way into the lymphatic system and how they choose between lymphatic and blood vessels for migration. Here we report that mammary tumor cells undergoing epithelial-mesenchymal transition (EMT) in response to transforming growth factor-beta (TGF-beta 1) become activated for targeted migration through the lymphatic system, similar to dendritic cells (DCs) during inflammation. EMT cells preferentially migrated toward lymphatic vessels compared with blood vessels, both in vivo and in 3D cultures. A mechanism of this targeted migration was traced to the capacity of TGF-beta 1 to promote CCR7/CCL21-mediated crosstalk between tumor cells and lymphatic endothelial cells. On one hand, TGF-beta 1 promoted CCR7 expression in EMT cells through p38 MAP kinase-mediated activation of the JunB transcription factor. Blockade of CCR7, or treatment with a p38 MAP kinase inhibitor, reduced lymphatic dissemination of EMT cells in syngeneic mice. On the other hand, TGF-beta 1 promoted CCL21 expression in lymphatic endothelial cells. CCL21 acted in a paracrine fashion to mediate chemotactic migration of EMT cells toward lymphatic endothelial cells. The results identify TGF-beta 1-induced EMT as a mechanism, which activates tumor cells for targeted, DC-like migration through the lymphatic system. Furthermore, it suggests that p38 MAP kinase inhibition may be a useful strategy to inhibit EMT and lymphogenic spread of tumor cells.
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| 10. |
- Arnold, TD, et al.
(författare)
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Excessive vascular sprouting underlies cerebral hemorrhage in mice lacking αVβ8-TGFβ signaling in the brain
- 2014
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Ingår i: Development (Cambridge, England). - : The Company of Biologists. - 1477-9129 .- 0950-1991. ; 141:23, s. 4489-4499
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Tidskriftsartikel (refereegranskat)abstract
- Vascular development of the central nervous system and blood-brain barrier (BBB) induction are closely linked processes. The role of factors that promote endothelial sprouting and vascular leak, such as vascular endothelial growth factor A, are well described, but the factors that suppress angiogenic sprouting and their impact on the BBB are poorly understood. Here, we show that integrin αVβ8 activates angiosuppressive TGFβ gradients in the brain, which inhibit endothelial cell sprouting. Loss of αVβ8 in the brain or downstream TGFβ1-TGFBR2-ALK5-Smad3 signaling in endothelial cells increases vascular sprouting, branching and proliferation, leading to vascular dysplasia and hemorrhage. Importantly, BBB function in Itgb8 mutants is intact during early stages of vascular dysgenesis before hemorrhage. By contrast, Pdgfbret/ret mice, which exhibit severe BBB disruption and vascular leak due to pericyte deficiency, have comparatively normal vascular morphogenesis and do not exhibit brain hemorrhage. Our data therefore suggest that abnormal vascular sprouting and patterning, not BBB dysfunction, underlie developmental cerebral hemorrhage.
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| 14. |
- Gaengel, K., et al.
(författare)
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The Sphingosine-1-Phosphate Receptor S1PR1 Restricts Sprouting Angiogenesis by Regulating the Interplay between VE-Cadherin and VEGFR2
- 2012
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Ingår i: Developmental Cell. - : Elsevier BV. - 1534-5807 .- 1878-1551. ; 23:3, s. 587-599
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Tidskriftsartikel (refereegranskat)abstract
- Angiogenesis, the process by which new blood vessels arise from preexisting ones, is critical for embryonic development and is an integral part of many disease processes. Recent studies have provided detailed information on how angiogenic sprouts initiate, elongate, and branch, but less is known about how these processes cease. Here, we show that S1PR1, a receptor for the blood-borne bioactive lipid sphingosine-1-phosphate (S1P), is critical for inhibition of angiogenesis and acquisition of vascular stability. Loss of S1PR1 leads to increased endothelial cell sprouting and the formation of ectopic vessel branches. Conversely, S1PR1 signaling inhibits angiogenic sprouting and enhances cell-to-cell adhesion. This correlates with inhibition of vascular endothelial growth factor-A (VEGF-A)-induced signaling and stabilization of vascular endothelial (VE)-cadherin localization at endothelial junctions. Our data suggest that S1PR1 signaling acts as a vascular-intrinsic stabilization mechanism, protecting developing blood vessels against aberrant angiogenic responses.
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| 19. |
- Jones, Gregory T., et al.
(författare)
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Meta-Analysis of Genome-Wide Association Studies for Abdominal Aortic Aneurysm Identifies Four New Disease-Specific Risk Loci
- 2017
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Ingår i: Circulation Research. - 0009-7330 .- 1524-4571. ; 120:2, s. 341-
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Tidskriftsartikel (refereegranskat)abstract
- Rationale: Abdominal aortic aneurysm (AAA) is a complex disease with both genetic and environmental risk factors. Together, 6 previously identified risk loci only explain a small proportion of the heritability of AAA. Objective: To identify additional AAA risk loci using data from all available genome-wide association studies. Methods and Results: Through a meta-analysis of 6 genome-wide association study data sets and a validation study totaling 10 204 cases and 107 766 controls, we identified 4 new AAA risk loci: 1q32.3 (SMYD2), 13q12.11 (LINC00540), 20q13.12 (near PCIF1/MMP9/ZNF335), and 21q22.2 (ERG). In various database searches, we observed no new associations between the lead AAA single nucleotide polymorphisms and coronary artery disease, blood pressure, lipids, or diabetes mellitus. Network analyses identified ERG, IL6R, and LDLR as modifiers of MMP9, with a direct interaction between ERG and MMP9. Conclusions: The 4 new risk loci for AAA seem to be specific for AAA compared with other cardiovascular diseases and related traits suggesting that traditional cardiovascular risk factor management may only have limited value in preventing the progression of aneurysmal disease.
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| 23. |
- Mäe, Maarja Andaloussi, et al.
(författare)
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Single-Cell Analysis of Blood-Brain Barrier Response to Pericyte Loss
- 2021
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Ingår i: Circulation Research. - : Lippincott Williams & Wilkins. - 0009-7330 .- 1524-4571. ; 128:4, s. E46-E62
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Tidskriftsartikel (refereegranskat)abstract
- Rationale: Pericytes are capillary mural cells playing a role in stabilizing newly formed blood vessels during development and tissue repair. Loss of pericytes has been described in several brain disorders, and genetically induced pericyte deficiency in the brain leads to increased macromolecular leakage across the blood-brain barrier (BBB). However, the molecular details of the endothelial response to pericyte deficiency remain elusive.Objective: To map the transcriptional changes in brain endothelial cells resulting from lack of pericyte contact at single-cell level and to correlate them with regional heterogeneities in BBB function and vascular phenotype.Methods and Results: We reveal transcriptional, morphological, and functional consequences of pericyte absence for brain endothelial cells using a combination of methodologies, including single-cell RNA sequencing, tracer analyses, and immunofluorescent detection of protein expression in pericyte-deficient adult Pdgfb(ret/ret) mice. We find that endothelial cells without pericyte contact retain a general BBB-specific gene expression profile, however, they acquire a venous-shifted molecular pattern and become transformed regarding the expression of numerous growth factors and regulatory proteins. Adult Pdgfb(ret/ret) brains display ongoing angiogenic sprouting without concomitant cell proliferation providing unique insights into the endothelial tip cell transcriptome. We also reveal heterogeneous modes of pericyte-deficient BBB impairment, where hotspot leakage sites display arteriolar-shifted identity and pinpoint putative BBB regulators. By testing the causal involvement of some of these using reverse genetics, we uncover a reinforcing role for angiopoietin 2 at the BBB.Conclusions: By elucidating the complexity of endothelial response to pericyte deficiency at cellular resolution, our study provides insight into the importance of brain pericytes for endothelial arterio-venous zonation, angiogenic quiescence, and a limited set of BBB functions. The BBB-reinforcing role of ANGPT2 (angiopoietin 2) is paradoxical given its wider role as TIE2 (TEK receptor tyrosine kinase) receptor antagonist and may suggest a unique and context-dependent function of ANGPT2 in the brain.
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| 24. |
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| 25. |
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| 26. |
- Pekny, M, et al.
(författare)
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Abnormal reaction to central nervous system injury in mice lacking glial fibrillary acidic protein and vimentin
- 1999
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Ingår i: The Journal of cell biology. - : Rockefeller University Press. - 0021-9525 .- 1540-8140. ; 145:3, s. 503-514
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Tidskriftsartikel (refereegranskat)abstract
- In response to injury of the central nervous system, astrocytes become reactive and express high levels of the intermediate filament (IF) proteins glial fibrillary acidic protein (GFAP), vimentin, and nestin. We have shown that astrocytes in mice deficient for both GFAP and vimentin (GFAP−/−vim−/−) cannot form IFs even when nestin is expressed and are thus devoid of IFs in their reactive state. Here, we have studied the reaction to injury in the central nervous system in GFAP−/−, vimentin−/−, or GFAP−/−vim−/− mice. Glial scar formation appeared normal after spinal cord or brain lesions in GFAP−/− or vimentin−/− mice, but was impaired in GFAP−/−vim−/− mice that developed less dense scars frequently accompanied by bleeding. These results show that GFAP and vimentin are required for proper glial scar formation in the injured central nervous system and that some degree of functional overlap exists between these IF proteins.
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| 32. |
- Rodin, S, et al.
(författare)
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Clonal culturing of human embryonic stem cells on laminin-521/E-cadherin matrix in defined and xeno-free environment
- 2014
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 5, s. 3195-
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Tidskriftsartikel (refereegranskat)abstract
- Lack of robust methods for establishment and expansion of pluripotent human embryonic stem (hES) cells still hampers development of cell therapy. Laminins (LN) are a family of highly cell-type specific basement membrane proteins important for cell adhesion, differentiation, migration and phenotype stability. Here we produce and isolate a human recombinant LN-521 isoform and develop a cell culture matrix containing LN-521 and E-cadherin, which both localize to stem cell niches in vivo. This matrix allows clonal derivation, clonal survival and long-term self-renewal of hES cells under completely chemically defined and xeno-free conditions without ROCK inhibitors. Neither LN-521 nor E-cadherin alone enable clonal survival of hES cells. The LN-521/E-cadherin matrix allows hES cell line derivation from blastocyst inner cell mass and single blastomere cells without a need to destroy the embryo. This method can facilitate the generation of hES cell lines for development of different cell types for regenerative medicine purposes.
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| 33. |
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| 35. |
- Siemsen, BL, et al.
(författare)
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Role of ramp2 in angiogenesis
- 2013
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Ingår i: ANGIOGENESIS. - 0969-6970. ; 16:1, s. 261-262
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)
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| 36. |
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| 38. |
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| 39. |
- Wang, She, et al.
(författare)
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Targeted disruption of the mouse PLC b3 gene results in defective preimplantation and tumor predisposition
- 1998
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Ingår i: FEBS Letters. - 0014-5793 .- 1873-3468. ; 441:2, s. 261-265
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Tidskriftsartikel (refereegranskat)abstract
- In order to investigate the biological function of phosphatidylinositol-specific phospholipase C (PLC) we generated mutant mice by gene targeting. Homozygous inactivation of PLCβ3 is lethal at embryonic day 2.5. These mutants show poor embryonic organization as well as reduced numbers of cells. Identical phenotypes were recorded in homozygous mutants generated from two independently targeted embryonic stem cell clones. Heterozygous mutant mice, however, are viable and fertile for at least two generations. We also showed that mouse PLCβ3 is expressed in unfertilized eggs, 3-cell and egg cylinder stages of embryos. In conclusion, these results indicate that PLCβ3 expression is essential for early mouse embryonic development.
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| 40. |
- Webb, Thomas R., et al.
(författare)
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Systematic Evaluation of Pleiotropy Identifies 6 Further Loci Associated With Coronary Artery Disease
- 2017
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Ingår i: Journal of the American College of Cardiology. - : Elsevier BV. - 0735-1097 .- 1558-3597. ; 69:7, s. 823-836
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND Genome-wide association studies have so far identified 56 loci associated with risk of coronary artery disease (CAD). Many CAD loci show pleiotropy; that is, they are also associated with other diseases or traits.OBJECTIVES This study sought to systematically test if genetic variants identified for non-CAD diseases/traits also associate with CAD and to undertake a comprehensive analysis of the extent of pleiotropy of all CAD loci.METHODS In discovery analyses involving 42,335 CAD cases and 78,240 control subjects we tested the association of 29,383 common (minor allele frequency >5%) single nucleotide polymorphisms available on the exome array, which included a substantial proportion of known or suspected single nucleotide polymorphisms associated with common diseases or traits as of 2011. Suggestive association signals were replicated in an additional 30,533 cases and 42,530 control subjects. To evaluate pleiotropy, we tested CAD loci for association with cardiovascular risk factors (lipid traits, blood pressure phenotypes, body mass index, diabetes, and smoking behavior), as well as with other diseases/traits through interrogation of currently available genome-wide association study catalogs.RESULTS We identified 6 new loci associated with CAD at genome-wide significance: on 2q37 (KCNJ13-GIGYF2), 6p21 (C2), 11p15 (MRVI1-CTR9), 12q13 (LRP1), 12q24 (SCARB1), and 16q13 (CETP). Risk allele frequencies ranged from 0.15 to 0.86, and odds ratio per copy of the risk allele ranged from 1.04 to 1.09. Of 62 new and known CAD loci, 24 (38.7%) showed statistical association with a traditional cardiovascular risk factor, with some showing multiple associations, and 29 (47%) showed associations at p < 1 x 10(-4) with a range of other diseases/traits.CONCLUSIONS We identified 6 loci associated with CAD at genome-wide significance. Several CAD loci show substantial pleiotropy, which may help us understand the mechanisms by which these loci affect CAD risk.
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| 41. |
- Zhou, K., et al.
(författare)
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An overlooked subset of Cx3cr1(wt/wt) microglia in the Cx3cr1(CreER-Eyfp/wt) mouse has a repopulation advantage over Cx3cr1(CreER-Eyfp/wt) microglia following microglial depletion
- 2022
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Ingår i: Journal of Neuroinflammation. - : Springer Science and Business Media LLC. - 1742-2094. ; 19:1
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Tidskriftsartikel (refereegranskat)abstract
- Background Fluorescent reporter labeling and promoter-driven Cre-recombinant technologies have facilitated cellular investigations of physiological and pathological processes, including the widespread use of the Cx3cr1(CreER-Eyfp/wt) mouse strain for studies of microglia. Methods Immunohistochemistry, Flow Cytometry, RNA sequencing and whole-genome sequencing were used to identify the subpopulation of microglia in Cx3cr1(CreER-Eyfp/wt) mouse brains. Genetically mediated microglia depletion using Cx3cr1(CreER-Eyfp/wt)Rosa26(DTA/wt) mice and CSF1 receptor inhibitor PLX3397 were used to deplete microglia. Primary microglia proliferation and migration assay were used for in vitro studies. Results We unexpectedly identified a subpopulation of microglia devoid of genetic modification, exhibiting higher Cx3cr1 and CX3CR1 expression than Cx3cr1(CreER-Eyfp/wt)Cre(+)Eyfp(+) microglia in Cx3cr1(CreER-Eyfp/wt) mouse brains, thus termed Cx3cr1(high)Cre(-)Eyfp(-) microglia. This subpopulation constituted less than 1% of all microglia under homeostatic conditions, but after Cre-driven DTA-mediated microglial depletion, Cx3cr1(high)Cre(-)Eyfp(-) microglia escaped depletion and proliferated extensively, eventually occupying one-third of the total microglial pool. We further demonstrated that the Cx3cr1(high)Cre(-)Eyfp(-) microglia had lost their genetic heterozygosity and become homozygous for wild-type Cx3cr1. Therefore, Cx3cr1(high)Cre(-)Eyfp(-) microglia are Cx3cr1(wt/wt)Cre(-)Eyfp(-). Finally, we demonstrated that CX3CL1-CX3CR1 signaling regulates microglial repopulation both in vivo and in vitro. Conclusions Our results raise a cautionary note regarding the use of Cx3cr1(CreER-Eyfp/wt) mouse strains, particularly when interpreting the results of fate mapping, and microglial depletion and repopulation studies.
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| 45. |
- Andrae, J, et al.
(författare)
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Role of platelet-derived growth factors in physiology and medicine
- 2008
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Ingår i: Genes & development. - : Cold Spring Harbor Laboratory. - 0890-9369 .- 1549-5477. ; 22:10, s. 1276-1312
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Tidskriftsartikel (refereegranskat)abstract
- Platelet-derived growth factors (PDGFs) and their receptors (PDGFRs) have served as prototypes for growth factor and receptor tyrosine kinase function for more than 25 years. Studies of PDGFs and PDGFRs in animal development have revealed roles for PDGFR-α signaling in gastrulation and in the development of the cranial and cardiac neural crest, gonads, lung, intestine, skin, CNS, and skeleton. Similarly, roles for PDGFR-β signaling have been established in blood vessel formation and early hematopoiesis. PDGF signaling is implicated in a range of diseases. Autocrine activation of PDGF signaling pathways is involved in certain gliomas, sarcomas, and leukemias. Paracrine PDGF signaling is commonly observed in epithelial cancers, where it triggers stromal recruitment and may be involved in epithelial–mesenchymal transition, thereby affecting tumor growth, angiogenesis, invasion, and metastasis. PDGFs drive pathological mesenchymal responses in vascular disorders such as atherosclerosis, restenosis, pulmonary hypertension, and retinal diseases, as well as in fibrotic diseases, including pulmonary fibrosis, liver cirrhosis, scleroderma, glomerulosclerosis, and cardiac fibrosis. We review basic aspects of the PDGF ligands and receptors, their developmental and pathological functions, principles of their pharmacological inhibition, and results using PDGF pathway-inhibitory or stimulatory drugs in preclinical and clinical contexts.
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| 49. |
- Armulik, A, et al.
(författare)
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Endothelial/pericyte interactions
- 2005
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Ingår i: Circulation research. - 1524-4571. ; 97:6, s. 512-523
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Tidskriftsartikel (refereegranskat)
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