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  1. Article: Mechanical forces in lymphatic vessel development: Focus on transcriptional regulation.

    Ujiie, Naoto / Kume, Tsutomu

    Frontiers in physiology

    2022  Volume 13, Page(s) 1066460

    Abstract: The lymphatic system is crucial for the maintenance of interstitial fluid and protein homeostasis. It has important roles in collecting excess plasma and interstitial fluid leaked from blood vessels, lipid absorption and transportation in the digestive ... ...

    Abstract The lymphatic system is crucial for the maintenance of interstitial fluid and protein homeostasis. It has important roles in collecting excess plasma and interstitial fluid leaked from blood vessels, lipid absorption and transportation in the digestive system, and immune surveillance and response. The development of lymphatic vessels begins during fetal life as lymphatic endothelial progenitor cells first differentiate into lymphatic endothelial cells (LECs) by expressing the master lymphatic vascular regulator, prospero-related homeobox 1 (PROX1). The lymphatic vasculature forms a hierarchical network that consists of blind-ended and unidirectional vessels. Although much progress has been made in the elucidation of the cellular and molecular mechanisms underlying the formation of the lymphatic vascular system, the causes of lymphatic vessel abnormalities and disease are poorly understood and complicated; specifically, the mechanistic basis for transcriptional dysregulation in lymphatic vessel development remains largely unclear. In this review, we discuss the recent advances in our understanding of the molecular and cellular mechanisms of lymphatic vascular development, including LEC differentiation, lymphangiogenesis, and valve formation, and the significance of mechanical forces in lymphatic vessels, with a focus on transcriptional regulation. We also summarize the current knowledge on epigenetic mechanisms of lymphatic gene expression.
    Language English
    Publishing date 2022-11-10
    Publishing country Switzerland
    Document type Journal Article ; Review
    ZDB-ID 2564217-0
    ISSN 1664-042X
    ISSN 1664-042X
    DOI 10.3389/fphys.2022.1066460
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  2. Article: FOXC1 and FOXC2 maintain mitral valve endothelial cell junctions, extracellular matrix, and lymphatic vessels to prevent myxomatous degeneration.

    Tan, Can / Kurup, Shreya / Dyakiv, Yaryna / Kume, Tsutomu

    bioRxiv : the preprint server for biology

    2023  

    Abstract: Background: Mitral valve (MV) disease including myxomatous degeneration is the most common form of valvular heart disease with an age-dependent frequency. Genetic evidence indicates mutations of the transcription factor : Methods: Adult mice carrying ...

    Abstract Background: Mitral valve (MV) disease including myxomatous degeneration is the most common form of valvular heart disease with an age-dependent frequency. Genetic evidence indicates mutations of the transcription factor
    Methods: Adult mice carrying tamoxifen-inducible, endothelial cell (EC)-specific, compound
    Results: EC-deletions of
    Conclusions: Our results indicate that
    Language English
    Publishing date 2023-08-30
    Publishing country United States
    Document type Preprint
    DOI 10.1101/2023.08.30.555455
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article: Editorial: Lymphatic system: organ specific functions in health and disease.

    Koltowska, Kaska / Jakus, Zoltán / Hong, Young-Kwon / Kume, Tsutomu

    Frontiers in cell and developmental biology

    2023  Volume 11, Page(s) 1224584

    Language English
    Publishing date 2023-10-23
    Publishing country Switzerland
    Document type Editorial
    ZDB-ID 2737824-X
    ISSN 2296-634X
    ISSN 2296-634X
    DOI 10.3389/fcell.2023.1224584
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  4. Article: Cardiac and intestinal tissue conduct developmental and reparative processes in response to lymphangiocrine signaling.

    Kurup, Shreya / Tan, Can / Kume, Tsutomu

    Frontiers in cell and developmental biology

    2023  Volume 11, Page(s) 1329770

    Abstract: Lymphatic vessels conduct a diverse range of activities to sustain the integrity of surrounding tissue. Besides facilitating the movement of lymph and its associated factors, lymphatic vessels are capable of producing tissue-specific responses to changes ...

    Abstract Lymphatic vessels conduct a diverse range of activities to sustain the integrity of surrounding tissue. Besides facilitating the movement of lymph and its associated factors, lymphatic vessels are capable of producing tissue-specific responses to changes within their microenvironment. Lymphatic endothelial cells (LECs) secrete paracrine signals that bind to neighboring cell-receptors, commencing an intracellular signaling cascade that preludes modifications to the organ tissue's structure and function. While the lymphangiocrine factors and the molecular and cellular mechanisms themselves are specific to the organ tissue, the crosstalk action between LECs and adjacent cells has been highlighted as a commonality in augmenting tissue regeneration within animal models of cardiac and intestinal disease. Lymphangiocrine secretions have been owed for subsequent improvements in organ function by optimizing the clearance of excess tissue fluid and immune cells and stimulating favorable tissue growth, whereas perturbations in lymphatic performance bring about the opposite. Newly published landmark studies have filled gaps in our understanding of cardiac and intestinal maintenance by revealing key players for lymphangiocrine processes. Here, we will expand upon those findings and review the nature of lymphangiocrine factors in the heart and intestine, emphasizing its involvement within an interconnected network that supports daily homeostasis and self-renewal following injury.
    Language English
    Publishing date 2023-12-21
    Publishing country Switzerland
    Document type Journal Article ; Review
    ZDB-ID 2737824-X
    ISSN 2296-634X
    ISSN 2296-634X
    DOI 10.3389/fcell.2023.1329770
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article: Foxc1

    Almubarak, Asra / Zhang, Qiuwan / Zhang, Cheng-Hai / Lassar, Andrew B / Kume, Tsutomu / Berry, Fred B

    bioRxiv : the preprint server for biology

    2023  

    Abstract: The forkhead box transcription factor ... ...

    Abstract The forkhead box transcription factor genes
    Language English
    Publishing date 2023-04-27
    Publishing country United States
    Document type Preprint
    DOI 10.1101/2023.04.26.538325
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  6. Article ; Online: Cardiac and intestinal tissue conduct developmental and reparative processes in response to lymphangiocrine signaling

    Shreya Kurup / Can Tan / Tsutomu Kume

    Frontiers in Cell and Developmental Biology, Vol

    2023  Volume 11

    Abstract: Lymphatic vessels conduct a diverse range of activities to sustain the integrity of surrounding tissue. Besides facilitating the movement of lymph and its associated factors, lymphatic vessels are capable of producing tissue-specific responses to changes ...

    Abstract Lymphatic vessels conduct a diverse range of activities to sustain the integrity of surrounding tissue. Besides facilitating the movement of lymph and its associated factors, lymphatic vessels are capable of producing tissue-specific responses to changes within their microenvironment. Lymphatic endothelial cells (LECs) secrete paracrine signals that bind to neighboring cell-receptors, commencing an intracellular signaling cascade that preludes modifications to the organ tissue’s structure and function. While the lymphangiocrine factors and the molecular and cellular mechanisms themselves are specific to the organ tissue, the crosstalk action between LECs and adjacent cells has been highlighted as a commonality in augmenting tissue regeneration within animal models of cardiac and intestinal disease. Lymphangiocrine secretions have been owed for subsequent improvements in organ function by optimizing the clearance of excess tissue fluid and immune cells and stimulating favorable tissue growth, whereas perturbations in lymphatic performance bring about the opposite. Newly published landmark studies have filled gaps in our understanding of cardiac and intestinal maintenance by revealing key players for lymphangiocrine processes. Here, we will expand upon those findings and review the nature of lymphangiocrine factors in the heart and intestine, emphasizing its involvement within an interconnected network that supports daily homeostasis and self-renewal following injury.
    Keywords lymphatic vessel ; lymphangiogenesis ; lymphangiocrine factors ; FOXC ; reelin ; R-spondins ; Biology (General) ; QH301-705.5
    Subject code 610
    Language English
    Publishing date 2023-12-01T00:00:00Z
    Publisher Frontiers Media S.A.
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  7. Article: Molecular Mechanisms Controlling Lymphatic Endothelial Junction Integrity.

    Norden, Pieter R / Kume, Tsutomu

    Frontiers in cell and developmental biology

    2021  Volume 8, Page(s) 627647

    Abstract: The lymphatic system is essential for lipid absorption/transport from the digestive system, maintenance of tissue fluid and protein homeostasis, and immune surveillance. Despite recent progress toward understanding the cellular and molecular mechanisms ... ...

    Abstract The lymphatic system is essential for lipid absorption/transport from the digestive system, maintenance of tissue fluid and protein homeostasis, and immune surveillance. Despite recent progress toward understanding the cellular and molecular mechanisms underlying the formation of the lymphatic vascular system, the nature of lymphatic vessel abnormalities and disease in humans is complex and poorly understood. The mature lymphatic vasculature forms a hierarchical network in which lymphatic endothelial cells (LECs) are joined by functionally specialized cell-cell junctions to maintain the integrity of lymphatic vessels. Blind-ended and highly permeable lymphatic capillaries drain interstitial fluid via discontinuous, button-like LEC junctions, whereas collecting lymphatic vessels, surrounded by intact basement membranes and lymphatic smooth muscle cells, have continuous, zipper-like LEC junctions to transport lymph to the blood circulatory system without leakage. In this review, we discuss the recent advances in our understanding of the mechanisms by which lymphatic button- and zipper-like junctions play critical roles in lymphatic permeability and function in a tissue- and organ-specific manner, including lacteals of the small intestine. We also provide current knowledge related to key pathways and factors such as VEGF and RhoA/ROCK signaling that control lymphatic endothelial cell junctional integrity.
    Language English
    Publishing date 2021-01-14
    Publishing country Switzerland
    Document type Journal Article ; Review
    ZDB-ID 2737824-X
    ISSN 2296-634X
    ISSN 2296-634X
    DOI 10.3389/fcell.2020.627647
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  8. Article ; Online: Molecular Mechanisms Controlling Lymphatic Endothelial Junction Integrity

    Pieter R. Norden / Tsutomu Kume

    Frontiers in Cell and Developmental Biology, Vol

    2021  Volume 8

    Abstract: The lymphatic system is essential for lipid absorption/transport from the digestive system, maintenance of tissue fluid and protein homeostasis, and immune surveillance. Despite recent progress toward understanding the cellular and molecular mechanisms ... ...

    Abstract The lymphatic system is essential for lipid absorption/transport from the digestive system, maintenance of tissue fluid and protein homeostasis, and immune surveillance. Despite recent progress toward understanding the cellular and molecular mechanisms underlying the formation of the lymphatic vascular system, the nature of lymphatic vessel abnormalities and disease in humans is complex and poorly understood. The mature lymphatic vasculature forms a hierarchical network in which lymphatic endothelial cells (LECs) are joined by functionally specialized cell-cell junctions to maintain the integrity of lymphatic vessels. Blind-ended and highly permeable lymphatic capillaries drain interstitial fluid via discontinuous, button-like LEC junctions, whereas collecting lymphatic vessels, surrounded by intact basement membranes and lymphatic smooth muscle cells, have continuous, zipper-like LEC junctions to transport lymph to the blood circulatory system without leakage. In this review, we discuss the recent advances in our understanding of the mechanisms by which lymphatic button- and zipper-like junctions play critical roles in lymphatic permeability and function in a tissue- and organ-specific manner, including lacteals of the small intestine. We also provide current knowledge related to key pathways and factors such as VEGF and RhoA/ROCK signaling that control lymphatic endothelial cell junctional integrity.
    Keywords lymphatic vessel junction ; button-like junction ; zipper-like junction ; VEGF signaling ; RhoA/ROCK ; Notch ; Biology (General) ; QH301-705.5
    Subject code 571
    Language English
    Publishing date 2021-01-01T00:00:00Z
    Publisher Frontiers Media S.A.
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  9. Article ; Online: Foxc1 and Foxc2 are indispensable for the maintenance of nephron and stromal progenitors in the developing kidney.

    Motojima, Masaru / Tanaka, Masayuki / Kume, Tsutomu

    Journal of cell science

    2022  Volume 135, Issue 19

    Abstract: Nephron development proceeds with reciprocal interactions among three layers: nephron progenitors (NPs), ureteric buds and stromal progenitors (SPs). We found that Foxc1 and Foxc2 (Foxc1/2) are expressed in NPs and SPs. Systemic deletion of Foxc1/2 2 ... ...

    Abstract Nephron development proceeds with reciprocal interactions among three layers: nephron progenitors (NPs), ureteric buds and stromal progenitors (SPs). We found that Foxc1 and Foxc2 (Foxc1/2) are expressed in NPs and SPs. Systemic deletion of Foxc1/2 2 days after the onset of metanephros development (embryonic day 13.5) resulted in the epithelialization of NPs and ectopic formation of renal vesicles. NP-specific deletion did not cause these phenotypes, indicating that Foxc1/2 in other cells (likely in SPs) contributed to the maintenance of NPs. Single-cell RNA-sequencing analysis revealed the existence of NP and SP subpopulations, the border between committed NPs and renewing NPs, and similarity between the cortical interstitium and vascular smooth muscle type cells. Integrated analysis of the control and Foxc1/2 knockout data indicated transformation of some NPs to strange cells expressing markers of the vascular endothelium, reduced numbers of self-renewing NP and SP populations, and downregulation of crucial genes for kidney development, such as Fgf20 and Frem1 in NPs, and Foxd1 and Sall1 in SPs. It also revealed upregulation of genes that were not usually expressed in NPs and SPs. Thus, Foxc1/2 maintain NPs and SPs by regulating the expression of multiple genes.
    MeSH term(s) Forkhead Transcription Factors/genetics ; Forkhead Transcription Factors/metabolism ; Kidney/metabolism ; Nephrons/metabolism ; Organogenesis ; RNA/metabolism
    Chemical Substances Forkhead Transcription Factors ; RNA (63231-63-0)
    Language English
    Publishing date 2022-09-29
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2993-2
    ISSN 1477-9137 ; 0021-9533
    ISSN (online) 1477-9137
    ISSN 0021-9533
    DOI 10.1242/jcs.260356
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  10. Article ; Online: Lymphatic vessel development: fluid flow and valve-forming cells.

    Kume, Tsutomu

    The Journal of clinical investigation

    2015  Volume 125, Issue 8, Page(s) 2924–2926

    Abstract: Hemodynamic forces regulate many aspects of blood vessel disease and development, including susceptibility to atherosclerosis and remodeling of primary blood vessels into a mature vascular network. Vessels of the lymphatic circulatory system are also ... ...

    Abstract Hemodynamic forces regulate many aspects of blood vessel disease and development, including susceptibility to atherosclerosis and remodeling of primary blood vessels into a mature vascular network. Vessels of the lymphatic circulatory system are also subjected to fluid flow-associated forces, but the molecular and cellular mechanisms by which these forces regulate the formation and maintenance of lymphatic vessels remain largely uncharacterized. This issue of the JCI includes two articles that begin to address how fluid flow influences lymphatic vessel development and function. Sweet et al. demonstrate that lymph flow is essential for the remodeling of primary lymphatic vessels, for ensuring the proper distribution of smooth muscle cells (SMCs), and for the development and maturation of lymphatic valves. Kazenwadel et al. show that flow-induced lymphatic valve development is initiated by the upregulation of GATA2, which has been linked to lymphedema in patients with Emberger syndrome. Together, these observations and future studies inspired by these results have potential to lead to the development of strategies for the treatment of lymphatic disorders.
    MeSH term(s) Animals ; GATA2 Transcription Factor/metabolism ; Humans ; Lymph/physiology ; Lymphatic Vessels/embryology ; Lymphedema/embryology ; Muscle, Smooth, Vascular/embryology ; Mutation ; Myocytes, Smooth Muscle/metabolism
    Chemical Substances GATA2 Transcription Factor
    Language English
    Publishing date 2015-08-03
    Publishing country United States
    Document type Comment ; Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 3067-3
    ISSN 1558-8238 ; 0021-9738
    ISSN (online) 1558-8238
    ISSN 0021-9738
    DOI 10.1172/JCI83189
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