| 1. |
- Ando, Koji, et al.
(författare)
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Peri-arterial specification of vascular mural cells from naive mesenchyme requires Notch signaling
- 2019
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Ingår i: Development. - : COMPANY BIOLOGISTS LTD. - 0950-1991 .- 1477-9129. ; 146:2
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Tidskriftsartikel (refereegranskat)abstract
- Mural cells (MCs) are essential for blood vessel stability and function; however, the mechanisms that regulate MC development remain incompletely understood, in particular those involved in MC specification. Here, we investigated the first steps of MC formation in zebrafish using transgenic reporters. Using pdgfrb and abcc9 reporters, we show that the onset of expression of abcc9, a pericyte marker in adult mice and zebrafish, occurs almost coincidentally with an increment in pdgfrb expression in peri-arterial mesenchymal cells, suggesting that these transcriptional changes mark the specification of MC lineage cells from naive pdgfrb(low) mesenchymal cells. The emergence of peri-arterial pdgfrb(high) MCs required Notch signaling. We found that pdgfrb-positive cells express notch2 in addition to notch3, and although depletion of notch2 or notch3 failed to block MC emergence, embryos depleted of both notch2 and notch3 lost mesoderm- as well as neural crest-derived pdgfrb(high) MCs. Using reporters that read out Notch signaling and Notch2 receptor cleavage, we show that Notch activation in the mesenchyme precedes specification into pdgfrb(high) MCs. Taken together, these results show that Notch signaling is necessary for peri-arterial MC specification.
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| 2. |
- Andrae, Johanna, et al.
(författare)
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A role for PDGF-C/PDGFR alpha signaling in the formation of the meningeal basement membranes surrounding the cerebral cortex
- 2016
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Ingår i: Biology Open. - : The Company of Biologists. - 2046-6390. ; 5:4, s. 461-474
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Tidskriftsartikel (refereegranskat)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.
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| 3. |
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| 4. |
- Betsholtz, Christer
(författare)
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Cell-cell signaling in blood vessel development and function
- 2018
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Ingår i: EMBO Molecular Medicine. - : EMBO. - 1757-4676 .- 1757-4684. ; 10:3
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- The blood vasculature is an organ pervading all other organs (almost). During vascular development, cell-cell signaling by extracellular ligands and cell surface receptors ensure that new vessels sprout into non-vascularized regions and simultaneously acquire organ-specific specializations and adaptations that match the local physiological needs. The vessels thereby specialize in their permeability, molecular transport between blood and tissue, and ability to regulate blood flow on demand. Over the past decades, we have learnt about the generic cell-cell signaling mechanisms governing angiogenic sprouting, mural cell recruitment, and vascular remodeling, and we have obtained the first insights into signals that induce and maintain vascular organotypicity. However, intra-organ vascular diversity and arterio-venous hierarchies complicate the molecular characterization of the vasculature's cellular building blocks. Single-cell RNA sequencing provides a way forward, as it allows elucidation at a genome-wide and quantitative level of the transcriptional diversity occurring within the same cell types at different anatomical positions and levels of arterio-venous hierarchy in the organs. In this Louis-Jeantet Prize Winner: Commentary, I give a brief overview of vascular development and how recent advances in the field pave the way for more systematic efforts to explore vascular functions in health and disease.
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| 5. |
- Betsholtz, Christer
(författare)
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Lipid transport and human brain development
- 2015
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 47:7, s. 699-701
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- How the human brain rapidly builds up its lipid content during brain growth and maintains its lipids in adulthood has remained elusive. Two new studies show that inactivating mutations in MFSD2A, known to be expressed specifically at the blood-brain barrier, lead to microcephaly, thereby offering a simple and surprising solution to an old enigma.
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| 6. |
- Betsholtz, Christer
(författare)
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Transcriptional control of endothelial energy
- 2016
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 529:7585, s. 160-161
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
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| 7. |
- Bovay, Esther, et al.
(författare)
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Multiple roles of lymphatic vessels in peripheral lymph node development
- 2018
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Ingår i: Journal of Experimental Medicine. - : Rockefeller University Press. - 0022-1007 .- 1540-9538. ; 215:11, s. 2760-2777
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Tidskriftsartikel (refereegranskat)abstract
- The mammalian lymphatic system consists of strategically located lymph nodes (LNs) embedded into a lymphatic vascular network. Mechanisms underlying development of this highly organized system are not fully understood. Using highresolution imaging, we show that lymphoid tissue inducer (LTi) cells initially transmigrate from veins at LN development sites using gaps in venous mural coverage. This process is independent of lymphatic vasculature, but lymphatic vessels are indispensable for the transport of LTi cells that egress from blood capillaries elsewhere and serve as an essential LN expansion reservoir. At later stages, lymphatic collecting vessels ensure efficient LTi cell transport and formation of the LN capsule and subcapsular sinus. Perinodal lymphatics also promote local interstitial flow, which cooperates with lymphotoxin-beta signaling to amplify stromal CXCL13 production and thereby promote LTi cell retention. Our data unify previous models of LN development by showing that lymphatics intervene at multiple points to assist LN expansion and identify a new role for mechanical forces in LN development.
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| 8. |
- Castro, Marco, et al.
(författare)
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CDC42 deletion elicits cerebral vascular malformations via increased MEKK3-dependent KLF4 expression
- 2019
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Ingår i: Circulation Research. - 0009-7330 .- 1524-4571. ; 124:8, s. 1240-1252
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Tidskriftsartikel (refereegranskat)abstract
- Rationale: Aberrant formation of blood vessels precedes a broad spectrum of vascular complications; however, the cellular and molecular events governing vascular malformations are not yet fully understood. Objective: Here, we investigated the role of CDC42 (cell division cycle 42) during vascular morphogenesis and its relative importance for the development of cerebrovascular malformations. Methods and Results: To avoid secondary systemic effects often associated with embryonic gene deletion, we generated an endothelial-specific and inducible knockout approach to study postnatal vascularization of the mouse brain. Postnatal endothelial-specific deletion of Cdc42 elicits cerebrovascular malformations reminiscent of cerebral cavernous malformations (CCMs). At the cellular level, loss of CDC42 function in brain endothelial cells (ECs) impairs their sprouting, branching morphogenesis, axial polarity, and normal dispersion within the brain tissue. Disruption of CDC42 does not alter EC proliferation, but malformations occur where EC proliferation is the most pronounced during brain development-the postnatal cerebellum-indicating that a high, naturally occurring EC proliferation provides a permissive state for the appearance of these malformations. Mechanistically, CDC42 depletion in ECs elicited increased MEKK3 (mitogen-activated protein kinase kinase kinase 3)-MEK5 (mitogen-activated protein kinase kinase 5)-ERK5 (extracellular signal-regulated kinase 5) signaling and consequent detrimental overexpression of KLF (Kruppel-like factor) 2 and KLF4, recapitulating the hallmark mechanism for CCM pathogenesis. Through genetic approaches, we demonstrate that the coinactivation of Klf4 reduces the severity of vascular malformations in Cdc42 mutant mice. Moreover, we show that CDC42 interacts with CCMs and that CCM3 promotes CDC42 activity in ECs. Conclusions: We show that endothelial-specific deletion of Cdc42 elicits CCM-like cerebrovascular malformations and that CDC42 is engaged in the CCM signaling network to restrain the MEKK3-MEK5-ERK5-KLF2/4 pathway.
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| 9. |
- Castro, Marco
(författare)
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Cellular and molecular roles for CDC42 in angiogenesis
- 2018
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Angiogenesis is the physiological process by which new blood vessels grow and critically depends on the interplay between the major vascular units: endothelial cells, pericytes and smooth muscle cells. Dysfunction and mispatterning of blood vessels are associated with the progression of many vascular complications, and therefore, understanding the causes of vascular dysmorphia is a central question in vascular biology. CDC42 is a small GTPase known to regulate a diverse array of cellular functions in endothelial cells, however, its contribution to vascular development in vivo remains incompletely understood. The overall aim of this thesis work is to investigate the role of CDC42 during angiogenesis in the central nervous system, using an inducible endothelial-specific Cdc42 knockout model.In Paper I, I investigate which CDC42-dependent functions operational in vivo are of relevance for angiogenic sprouting, and how they contribute to blood vessel morphogenesis. Analysis of distinct cellular behaviours shows that CDC42 is critically required for proper EC dispersion in the vasculature and that it regulates sprouting angiogenesis and endothelial axial polarity.In Paper II, I explore the in vivo consequences of Cdc42 deletion for vascular morphogenesis, leading to the appearance of capillary-venous malformations in the brain, resembling the human disease of cerebral cavernous malformations. I aimed to understand how this type of vascular malformations arise and was been able to identify the MEKK3-ERK5-KLF2/4 molecular signalling pathway and other cellular events as the trigger factors that may be responsible for these malformations.Paper III redirects focus to the physiological roles of another protein, GPR116, in modulating blood-brain barrier permeability and pathologic angiogenesis in the central nervous system.In summary, these findings reveal crucial roles of endothelial CDC42 during angiogenesis and further uncover its potential relevance in the molecular pathogenesis of cerebrovascular malformations.
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| 10. |
- Dang, Thanh Chung, et al.
(författare)
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Powerful Homeostatic Control of Oligodendroglial Lineage by PDGFR alpha in Adult Brain
- 2019
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Ingår i: Cell Reports. - : CELL PRESS. - 2211-1247. ; 27:4, s. 1073-1089
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Tidskriftsartikel (refereegranskat)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.
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