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  1. Article ; Online: Toward a granular molecular-anatomic map of the blood vasculature - single-cell RNA sequencing makes the leap.

    Betsholtz, Christer

    Upsala journal of medical sciences

    2022  Volume 127

    Abstract: Single-cell RNA sequencing (scRNAseq) marks the birth of a new era in physiology and medicine. Within foreseeable future, we will know exactly what genes are expressed - and at what levels - in all the different cell types and subtypes that make up our ... ...

    Abstract Single-cell RNA sequencing (scRNAseq) marks the birth of a new era in physiology and medicine. Within foreseeable future, we will know exactly what genes are expressed - and at what levels - in all the different cell types and subtypes that make up our bodies. We will also learn how a particular cell state, whether it occurs during development, tissue repair, or disease, reflects precise changes in gene expression. While profoundly impacting all areas of life science, scRNAseq may lead to a particular leap in vascular biology research. Blood vessels pervade and fulfill essential functions in all organs, but the functions differ. Innumerable organ-specific vascular adaptations and specializations are required. These, in turn, are dictated by differential gene expression by the two principal cellular building blocks of blood vessels: endothelial cells and mural cells. An
    MeSH term(s) Humans ; Endothelial Cells/metabolism ; Neovascularization, Pathologic/genetics ; Neovascularization, Pathologic/metabolism ; Brain ; Liver ; Sequence Analysis, RNA
    Language English
    Publishing date 2022-10-21
    Publishing country Sweden
    Document type Journal Article ; Review
    ZDB-ID 183949-4
    ISSN 2000-1967 ; 0300-9734
    ISSN (online) 2000-1967
    ISSN 0300-9734
    DOI 10.48101/ujms.v127.9051
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  2. Article ; Online: Toward a granular molecular-anatomic map of the blood vasculature – single-cell RNA sequencing makes the leap

    Christer Betsholtz

    Upsala Journal of Medical Sciences, Vol 127, Pp 1-

    2022  Volume 14

    Abstract: Single-cell RNA sequencing (scRNAseq) marks the birth of a new era in physiology and medicine. Within foreseeable future, we will know exactly what genes are expressed – and at what levels – in all the different cell types and subtypes that make up our ... ...

    Abstract Single-cell RNA sequencing (scRNAseq) marks the birth of a new era in physiology and medicine. Within foreseeable future, we will know exactly what genes are expressed – and at what levels – in all the different cell types and subtypes that make up our bodies. We will also learn how a particular cell state, whether it occurs during development, tissue repair, or disease, reflects precise changes in gene expression. While profoundly impacting all areas of life science, scRNAseq may lead to a particular leap in vascular biology research. Blood vessels pervade and fulfill essential functions in all organs, but the functions differ. Innumerable organ-specific vascular adaptations and specializations are required. These, in turn, are dictated by differential gene expression by the two principal cellular building blocks of blood vessels: endothelial cells and mural cells. An organotypic vasculature is essential for functions as diverse as thinking, gas exchange, urine excretion, and xenobiotic detoxification in the brain, lung, kidney, and liver, respectively. In addition to the organotypicity, vascular cells also differ along the vascular arterio-venous axis, referred to as zonation, differences that are essential for the regulation of blood pressure and flow. Moreover, gene expression-based molecular changes dictate states of cellular activity, necessary for angiogenesis, vascular permeability, and immune cell trafficking, i.e. functions necessary for development, inflammation, and repair. These different levels of cellular heterogeneity create a nearly infinite phenotypic diversity among vascular cells. In this review, I summarize and exemplify what scRNAseq has brought to the picture in just a few years and point out where it will take us.
    Keywords single-cell rna sequencing ; endothelial cells ; mural cells ; zonation ; organotypicity ; cell stress ; Medicine ; R
    Subject code 610
    Language English
    Publishing date 2022-10-01T00:00:00Z
    Publisher Upsala Medical Society
    Document type Article ; Online
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  3. Article ; Online: Cell-cell signaling in blood vessel development and function.

    Betsholtz, Christer

    EMBO molecular medicine

    2018  Volume 10, Issue 3

    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 ... ...

    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
    MeSH term(s) Animals ; Blood Vessels/cytology ; Blood Vessels/physiology ; Cell Communication ; Endothelial Cells/cytology ; Humans ; Models, Biological ; Neovascularization, Physiologic ; Signal Transduction
    Language English
    Publishing date 2018-01-24
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2467145-9
    ISSN 1757-4684 ; 1757-4676
    ISSN (online) 1757-4684
    ISSN 1757-4676
    DOI 10.15252/emmm.201708610
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  4. Article ; Online: Cell–cell signaling in blood vessel development and function

    Christer Betsholtz

    EMBO Molecular Medicine, Vol 10, Iss 3, Pp n/a-n/a (2018)

    2018  

    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 ... ...

    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.
    Keywords Medicine (General) ; R5-920 ; Genetics ; QH426-470
    Subject code 571
    Language English
    Publishing date 2018-03-01T00:00:00Z
    Publisher Wiley
    Document type Article ; Online
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  5. Article ; Online: Cellular Origin of Sporadic CCMs.

    Betsholtz, Christer / Gaengel, Konstantin / Mäkinen, Taija

    The New England journal of medicine

    2022  Volume 386, Issue 13, Page(s) 1291

    MeSH term(s) Humans ; Intellectual Disability ; Micrognathism ; Ribs
    Language English
    Publishing date 2022-03-29
    Publishing country United States
    Document type Letter ; Comment
    ZDB-ID 207154-x
    ISSN 1533-4406 ; 0028-4793
    ISSN (online) 1533-4406
    ISSN 0028-4793
    DOI 10.1056/NEJMc2117812
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  6. Article ; Online: Vascular biology: Transcriptional control of endothelial energy.

    Betsholtz, Christer

    Nature

    2016  Volume 529, Issue 7585, Page(s) 160–161

    MeSH term(s) Animals ; Endothelium, Vascular/growth & development ; Endothelium, Vascular/metabolism ; Female ; Forkhead Box Protein O1 ; Forkhead Transcription Factors/metabolism ; Humans ; Male
    Chemical Substances FOXO1 protein, human ; Forkhead Box Protein O1 ; Forkhead Transcription Factors ; Foxo1 protein, mouse
    Language English
    Publishing date 2016-01-14
    Publishing country England
    Document type Journal Article ; Comment
    ZDB-ID 120714-3
    ISSN 1476-4687 ; 0028-0836
    ISSN (online) 1476-4687
    ISSN 0028-0836
    DOI 10.1038/nature16866
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  7. Article ; Online: Tumor-specific migration routes of xenotransplanted human glioblastoma cells in mouse brain.

    Gupta, Rajesh Kumar / Niklasson, Mia / Bergström, Tobias / Segerman, Anna / Betsholtz, Christer / Westermark, Bengt

    Scientific reports

    2024  Volume 14, Issue 1, Page(s) 864

    Abstract: The migration of neural progenitor cells (NPCs) to their final destination during development follows well-defined pathways, such as along blood vessels. Cells originating from the highly malignant tumor glioblastoma (GBM) seem to exploit similar routes ... ...

    Abstract The migration of neural progenitor cells (NPCs) to their final destination during development follows well-defined pathways, such as along blood vessels. Cells originating from the highly malignant tumor glioblastoma (GBM) seem to exploit similar routes for infiltrating the brain parenchyma. In this report, we have examined the migration of GBM cells using three-dimensional high-resolution confocal microscopy in brain tumors derived from eight different human GBM cell lines xenografted into immunodeficient mice. The primary invasion routes identified were long-distance migration along white matter tracts and local migration along blood vessels. We found that GBM cells in the majority of tumors (6 out of 8) did not exhibit association with blood vessels. These tumors, derived from low lamin A/C expressing GBM cells, were comparatively highly diffusive and invasive. Conversely, in 2 out of 8 tumors, we noted perivascular invasion and displacement of astrocyte end-feet. These tumors exhibited less diffusive migration, grew as solid tumors, and were distinguished by elevated expression of lamin A/C. We conclude that the migration pattern of glioblastoma is distinctly tumor cell-specific. Furthermore, the ability to invade the confined spaces within white matter tracts may necessitate low expression of lamin A/C, contributing to increased nuclear plasticity. This study highlights the role of GBM heterogeneity in driving the aggressive growth of glioblastoma.
    MeSH term(s) Humans ; Animals ; Mice ; Glioblastoma ; Lamin Type A ; Brain Neoplasms ; Brain ; Aggression
    Chemical Substances Lamin Type A
    Language English
    Publishing date 2024-01-09
    Publishing country England
    Document type Journal Article
    ZDB-ID 2615211-3
    ISSN 2045-2322 ; 2045-2322
    ISSN (online) 2045-2322
    ISSN 2045-2322
    DOI 10.1038/s41598-023-51063-7
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  8. Article ; Online: Identification, discrimination and heterogeneity of fibroblasts.

    Lendahl, Urban / Muhl, Lars / Betsholtz, Christer

    Nature communications

    2022  Volume 13, Issue 1, Page(s) 3409

    Abstract: Fibroblasts, the principal cell type of connective tissue, secrete extracellular matrix components during tissue development, homeostasis, repair and disease. Despite this crucial role, the identification and distinction of fibroblasts from other cell ... ...

    Abstract Fibroblasts, the principal cell type of connective tissue, secrete extracellular matrix components during tissue development, homeostasis, repair and disease. Despite this crucial role, the identification and distinction of fibroblasts from other cell types are challenging and laden with caveats. Rapid progress in single-cell transcriptomics now yields detailed molecular portraits of fibroblasts and other cell types in our bodies, which complement and enrich classical histological and immunological descriptions, improve cell class definitions and guide further studies on the functional heterogeneity of cell subtypes and states, origins and fates in physiological and pathological processes. In this review, we summarize and discuss recent advances in the understanding of fibroblast identification and heterogeneity and how they discriminate from other cell types.
    MeSH term(s) Connective Tissue ; Fibroblasts/metabolism
    Language English
    Publishing date 2022-06-14
    Publishing country England
    Document type Journal Article ; Review ; Research Support, Non-U.S. Gov't
    ZDB-ID 2553671-0
    ISSN 2041-1723 ; 2041-1723
    ISSN (online) 2041-1723
    ISSN 2041-1723
    DOI 10.1038/s41467-022-30633-9
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  9. Article ; Online: Lipid transport and human brain development.

    Betsholtz, Christer

    Nature genetics

    2015  Volume 47, Issue 7, Page(s) 699–701

    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 ... ...

    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.
    MeSH term(s) Biological Transport ; Brain/growth & development ; Brain/metabolism ; Humans ; Lipid Metabolism ; Microcephaly/genetics ; Tumor Suppressor Proteins/genetics
    Chemical Substances MFSD2A protein, human ; Tumor Suppressor Proteins
    Language English
    Publishing date 2015-07
    Publishing country United States
    Document type Journal Article
    ZDB-ID 1108734-1
    ISSN 1546-1718 ; 1061-4036
    ISSN (online) 1546-1718
    ISSN 1061-4036
    DOI 10.1038/ng.3348
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  10. Article ; Online: Tumor-specific migration routes of xenotransplanted human glioblastoma cells in mouse brain

    Rajesh Kumar Gupta / Mia Niklasson / Tobias Bergström / Anna Segerman / Christer Betsholtz / Bengt Westermark

    Scientific Reports, Vol 14, Iss 1, Pp 1-

    2024  Volume 11

    Abstract: Abstract The migration of neural progenitor cells (NPCs) to their final destination during development follows well-defined pathways, such as along blood vessels. Cells originating from the highly malignant tumor glioblastoma (GBM) seem to exploit ... ...

    Abstract Abstract The migration of neural progenitor cells (NPCs) to their final destination during development follows well-defined pathways, such as along blood vessels. Cells originating from the highly malignant tumor glioblastoma (GBM) seem to exploit similar routes for infiltrating the brain parenchyma. In this report, we have examined the migration of GBM cells using three-dimensional high-resolution confocal microscopy in brain tumors derived from eight different human GBM cell lines xenografted into immunodeficient mice. The primary invasion routes identified were long-distance migration along white matter tracts and local migration along blood vessels. We found that GBM cells in the majority of tumors (6 out of 8) did not exhibit association with blood vessels. These tumors, derived from low lamin A/C expressing GBM cells, were comparatively highly diffusive and invasive. Conversely, in 2 out of 8 tumors, we noted perivascular invasion and displacement of astrocyte end-feet. These tumors exhibited less diffusive migration, grew as solid tumors, and were distinguished by elevated expression of lamin A/C. We conclude that the migration pattern of glioblastoma is distinctly tumor cell-specific. Furthermore, the ability to invade the confined spaces within white matter tracts may necessitate low expression of lamin A/C, contributing to increased nuclear plasticity. This study highlights the role of GBM heterogeneity in driving the aggressive growth of glioblastoma.
    Keywords Medicine ; R ; Science ; Q
    Subject code 570
    Language English
    Publishing date 2024-01-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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