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Suh, S. H., Choe, K., Hong, S. P., Jeong, S.-h., Mäkinen, T., Kim, K. S., . . . Song, J.-H. (2019). Gut microbiota regulates lacteal integrity by inducing VEGF-C in intestinal villus macrophages. EMBO Reports, 20(4), Article ID e46927.
Open this publication in new window or tab >>Gut microbiota regulates lacteal integrity by inducing VEGF-C in intestinal villus macrophages
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2019 (English)In: EMBO Reports, ISSN 1469-221X, E-ISSN 1469-3178, Vol. 20, no 4, article id e46927Article in journal (Refereed) Published
Abstract [en]

A lacteal is a blunt-ended, long, tube-like lymphatic vessel located in the center of each intestinal villus that provides a unique route for drainage of absorbed lipids from the small intestine. However, key regulators for maintaining lacteal integrity are poorly understood. Here, we explore whether and how the gut microbiota regulates lacteal integrity. Germ depletion by antibiotic treatment triggers lacteal regression during adulthood and delays lacteal maturation during the postnatal period. In accordance with compromised lipid absorption, the button-like junction between lymphatic endothelial cells, which is ultrastructurally open to permit free entry of dietary lipids into lacteals, is significantly reduced in lacteals of germ-depleted mice. Lacteal defects are also found in germ-free mice, but conventionalization of germ-free mice leads to normalization of lacteals. Mechanistically, VEGF-C secreted from villus macrophages upon MyD88-dependent recognition of microbes and their products is a main factor in lacteal integrity. Collectively, we conclude that the gut microbiota is a crucial regulator for lacteal integrity by endowing its unique microenvironment and regulating villus macrophages in small intestine.

Place, publisher, year, edition, pages
WILEY, 2019
Keywords
intestinal lymphatic vasculature, lacteal, macrophage, microbiota, VEGF-C
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-382513 (URN)10.15252/embr.201846927 (DOI)000463235300015 ()30783017 (PubMedID)
Available from: 2019-04-30 Created: 2019-04-30 Last updated: 2019-04-30Bibliographically approved
Urner, S., Planas-Paz, L., Hilger, L. S., Henning, C., Branopolski, A., Kelly-Goss, M., . . . Lammert, E. (2019). Identification of ILK as a critical regulator of VEGFR3 signalling and lymphatic vascular growth. EMBO Journal, 38(2), Article ID e99322.
Open this publication in new window or tab >>Identification of ILK as a critical regulator of VEGFR3 signalling and lymphatic vascular growth
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2019 (English)In: EMBO Journal, ISSN 0261-4189, E-ISSN 1460-2075, Vol. 38, no 2, article id e99322Article in journal (Refereed) Published
Abstract [en]

Vascular endothelial growth factor receptor-3 (VEGFR3) signalling promotes lymphangiogenesis. While there are many reported mechanisms of VEGFR3 activation, there is little understanding of how VEGFR3 signalling is attenuated to prevent lymphatic vascular overgrowth and ensure proper lymph vessel development. Here, we show that endothelial cell-specific depletion of integrin-linked kinase (ILK) in mouse embryos hyper-activates VEGFR3 signalling and leads to overgrowth of the jugular lymph sacs/primordial thoracic ducts, oedema and embryonic lethality. Lymphatic endothelial cell (LEC)-specific deletion of Ilk in adult mice initiates lymphatic vascular expansion in different organs, including cornea, skin and myocardium. Knockdown of ILK in human LECs triggers VEGFR3 tyrosine phosphorylation and proliferation. ILK is further found to impede interactions between VEGFR3 and beta 1 integrin in vitro and in vivo, and endothelial cell-specific deletion of an Itgb1 allele rescues the excessive lymphatic vascular growth observed upon ILK depletion. Finally, mechanical stimulation disrupts the assembly of ILK and beta 1 integrin, releasing the integrin to enable its interaction with VEGFR3. Our data suggest that ILK facilitates mechanically regulated VEGFR3 signalling via controlling its interaction with beta 1 integrin and thus ensures proper development of lymphatic vessels.

Place, publisher, year, edition, pages
WILEY, 2019
Keywords
integrin-linked kinase, lymphatic vasculature, mechanical stimulation, VEGFR3, beta 1 integrin
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-375868 (URN)10.15252/embj.201899322 (DOI)000455915300003 ()30518533 (PubMedID)
Funder
German Research Foundation (DFG), LA1216/5-1German Research Foundation (DFG), MO2562/1-2German Research Foundation (DFG), IRTG 1902German Research Foundation (DFG), SFB 1116
Available from: 2019-02-04 Created: 2019-02-04 Last updated: 2019-02-04Bibliographically approved
Mäkinen, T. (2019). Neurobiology: A Drain At The Base Of The Brain. Nature, 572(7767), 34-35
Open this publication in new window or tab >>Neurobiology: A Drain At The Base Of The Brain
2019 (English)In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 572, no 7767, p. 34-35Article in journal, Editorial material (Other academic) Published
Abstract [en]

A set of lymphatic vessels that wrap around the base of the mouse brain have been shown to drain fluid from the brain into the peripheral lymphatic system, and to exhibit a decline in function with ageing.

National Category
Neurology
Identifiers
urn:nbn:se:uu:diva-392896 (URN)10.1038/d41586-019-02166-7 (DOI)000478017900027 ()31358927 (PubMedID)
Note

Title of web version: Lymphatic vessels at the base of the mouse brain provide direct drainage to the periphery

Available from: 2019-09-10 Created: 2019-09-10 Last updated: 2019-09-10Bibliographically approved
Cho, H., Kim, J., Ahn, J. H., Hong, Y.-K., Mäkinen, T., Lim, D.-S. & Koh, G. Y. (2019). YAP and TAZ Negatively Regulate Prox1 During Developmental and Pathologic Lymphangiogenesis. Circulation Research, 124(2), 225-242
Open this publication in new window or tab >>YAP and TAZ Negatively Regulate Prox1 During Developmental and Pathologic Lymphangiogenesis
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2019 (English)In: Circulation Research, ISSN 0009-7330, E-ISSN 1524-4571, Vol. 124, no 2, p. 225-242Article in journal (Refereed) Published
Abstract [en]

Rationale: The Hippo pathway governs cellular differentiation, morphogenesis, and homeostasis, but how it regulates these processes in lymphatic vessels is unknown. Objective: We aimed to reveal the role of the final effectors of the Hippo pathway, YAP (Yes-associated protein) and TAZ (transcriptional coactivator with PDZ-binding motif), in lymphatic endothelial cell (LEC) differentiation, morphogenesis, and homeostasis. Methods and Results: During mouse embryonic development, LEC-specific depletion of Yap/Taz disturbed both plexus patterning and valve initiation with upregulated Prox1 (prospero homeobox 1). Conversely, LEC-specific YAP/TAZ hyperactivation impaired lymphatic specification and restricted lymphatic sprouting with profoundly downregulated Prox1. Notably, lymphatic YAP/TAZ depletion or hyperactivation aggravated or attenuated pathological lymphangiogenesis in mouse cornea. Mechanistically, VEGF (vascular endothelial growth factor)-C activated canonical Hippo signaling pathway in LECs. Indeed, repression of PROX1 transcription by YAP/TAZ hyperactivation was mediated by recruitment of NuRD (nucleosome remodeling and histone deacetylase) complex and endogenous binding activity of TEAD (TEA domain family members) to the PROX1 promoter. Furthermore, YAP/TAZ hyperactivation enhanced MYC signaling and inhibited CDKN1C, leading to cell cycle dysregulation and aberrant proliferation. Conclusions: We find that YAP and TAZ play promoting roles in remodeling lymphatic plexus patterning and postnatal lymphatic valve maintenance by negatively regulating Prox1 expression. We further show that YAP and TAZ act as plastic regulators of lymphatic identity and define the Hippo signaling-mediated PROX1 transcriptional programing as a novel dynamic checkpoint underlying LEC plasticity and pathophysiology.

Place, publisher, year, edition, pages
Lippincott Williams & Wilkins, 2019
Keywords
developmental biology, endothelial cells, lymphatic vessels, vascular endothelial growth factor C, vascular remodeling
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-387567 (URN)10.1161/CIRCRESAHA.118.313707 (DOI)000469341100016 ()30582452 (PubMedID)
Available from: 2019-06-24 Created: 2019-06-24 Last updated: 2019-06-24Bibliographically approved
Haegerling, R., Hoppe, E., Dierkes, C., Stehling, M., Mäkinen, T., Butz, S., . . . Kiefer, F. (2018). Distinct roles of VE-cadherin for development and maintenance of specific lymph vessel beds. EMBO Journal, 37(22), Article ID e98271.
Open this publication in new window or tab >>Distinct roles of VE-cadherin for development and maintenance of specific lymph vessel beds
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2018 (English)In: EMBO Journal, ISSN 0261-4189, E-ISSN 1460-2075, Vol. 37, no 22, article id e98271Article in journal (Refereed) Published
Abstract [en]

Endothelial cells line blood and lymphatic vessels and form intercellular junctions, which preserve vessel structure and integrity. The vascular endothelial cadherin, VE-cadherin, mediates endothelial adhesion and is indispensible for blood vessel development and permeability regulation. However, its requirement for lymphatic vessels has not been addressed. During development, VE-cadherin deletion in lymphatic endothelial cells resulted in abortive lymphangiogenesis, edema, and prenatal death. Unexpectedly, inducible postnatal or adult deletion elicited vessel bed-specific responses. Mature dermal lymph vessels resisted VE-cadherin loss and maintained button junctions, which was associated with an upregulation of junctional molecules. Very different, mesenteric lymphatic collectors deteriorated and formed a strongly hyperplastic layer of lymphatic endothelial cells on the mesothelium. This massive hyperproliferation may have been favored by high mesenteric VEGF-C expression and was associated with VEGFR-3 phosphorylation and upregulation of the transcriptional activator TAZ. Finally, intestinal lacteals fragmented into cysts or became highly distended possibly as a consequence of the mesenteric defects. Taken together, we demonstrate here the importance of VE-cadherin for lymphatic vessel development and maintenance, which is however remarkably vessel bed-specific.

Place, publisher, year, edition, pages
WILEY, 2018
Keywords
lymph vessels, lymphatic valves, vascular heterogeneity, VE-cadherin, YAP/TAZ
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-371879 (URN)10.15252/embj.201798271 (DOI)000450263600007 ()30297530 (PubMedID)
Available from: 2019-01-07 Created: 2019-01-07 Last updated: 2019-01-07Bibliographically approved
Zhang, Y., Ulvmar, M. H., Stanczuk, L., Martinez-Corral, I., Frye, M., Alitalo, K. & Mäkinen, T. (2018). Heterogeneity in VEGFR3 levels drives lymphatic vessel hyperplasia through cell-autonomous and non-cell-autonomous mechanisms. Nature Communications, 9(1), Article ID 1296.
Open this publication in new window or tab >>Heterogeneity in VEGFR3 levels drives lymphatic vessel hyperplasia through cell-autonomous and non-cell-autonomous mechanisms
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2018 (English)In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 9, no 1, article id 1296Article in journal (Refereed) Published
Abstract [en]

Incomplete delivery to the target cells is an obstacle for successful gene therapy approaches. Here we show unexpected effects of incomplete targeting, by demonstrating how heterogeneous inhibition of a growth promoting signaling pathway promotes tissue hyperplasia. We studied the function of the lymphangiogenic VEGFR3 receptor during embryonic and post-natal development. Inducible genetic deletion of Vegfr3 in lymphatic endothelial cells (LECs) leads to selection of non-targeted VEGFR3+cells at vessel tips, indicating an indispensable cell-autonomous function in migrating tip cells. Although Vegfr3 deletion results in lymphatic hypoplasia in mouse embryos, incomplete deletion during post-natal development instead causes excessive lymphangiogenesis. Analysis of mosaically targeted endothelium shows that VEGFR3-LECs non-cell-autonomously drive abnormal vessel anastomosis and hyperplasia by inducing proliferation of non-targeted VEGFR3+LECs through cell-contact-dependent reduction of Notch signaling. Heterogeneity in VEGFR3 levels thus drives vessel hyperplasia, which has implications for the understanding of mechanisms of developmental and pathological tissue growth.

National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-348896 (URN)10.1038/s41467-018-03692-0 (DOI)000429003400001 ()29615616 (PubMedID)
Funder
Swedish Research Council, 542-2014-3535EU, European Research Council, ERC-2014-CoG-646849Knut and Alice Wallenberg Foundation, 2015.0030Stiftelsen G A Johanssons Minnesfond
Available from: 2018-04-18 Created: 2018-04-18 Last updated: 2018-06-13Bibliographically approved
Frye, M., Taddei, A., Dierkes, C., Martinez-Corral, I., Fielden, M., Ortsäter, H., . . . Mäkinen, T. (2018). Matrix stiffness controls lymphatic vessel formation through regulation of a GATA2-dependent transcriptional program. Nature Communications, 9, Article ID 1511.
Open this publication in new window or tab >>Matrix stiffness controls lymphatic vessel formation through regulation of a GATA2-dependent transcriptional program
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2018 (English)In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 9, article id 1511Article in journal (Refereed) Published
Abstract [en]

Tissue and vessel wall stiffening alters endothelial cell properties and contributes to vascular dysfunction. However, whether extracellular matrix (ECM) stiffness impacts vascular development is not known. Here we show that matrix stiffness controls lymphatic vascular morphogenesis. Atomic force microscopy measurements in mouse embryos reveal that venous lymphatic endothelial cell (LEC) progenitors experience a decrease in substrate stiffness upon migration out of the cardinal vein, which induces a GATA2-dependent transcriptional program required to form the first lymphatic vessels. Transcriptome analysis shows that LECs grown on a soft matrix exhibit increased GATA2 expression and a GATA2-dependent upregulation of genes involved in cell migration and lymphangiogenesis, including VEGFR3. Analyses of mouse models demonstrate a cell-autonomous function of GATA2 in regulating LEC responsiveness to VEGF-C and in controlling LEC migration and sprouting in vivo. Our study thus uncovers a mechanism by which ECM stiffness dictates the migratory behavior of LECs during early lymphatic development.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP, 2018
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-352466 (URN)10.1038/s41467-018-03959-6 (DOI)000430196200006 ()29666442 (PubMedID)
Funder
Swedish Research Council, D0368601]Swedish Research Council, 542-2014-3535]Swedish Cancer Society, CAN 2013/387EU, European Research Council, ERC-2014-CoG-646849Wellcome trust, FC001057
Available from: 2018-06-07 Created: 2018-06-07 Last updated: 2018-06-07Bibliographically approved
Gramolelli, S., Cheng, J., Martinez-Corral, I., Vaha-Koskela, M., Elbasani, E., Kaivanto, E., . . . Ojala, P. M. (2018). PROX1 is a transcriptional regulator of MMP14. Scientific Reports, 8, Article ID 9531.
Open this publication in new window or tab >>PROX1 is a transcriptional regulator of MMP14
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2018 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, article id 9531Article in journal (Refereed) Published
Abstract [en]

The transcription factor PROX1 is essential for development and cell fate specification. Its function in cancer is context-dependent since PROX1 has been shown to play both oncogenic and tumour suppressive roles. Here, we show that PROX1 suppresses the transcription of MMP14, a metalloprotease involved in angiogenesis and cancer invasion, by binding and suppressing the activity of MMP14 promoter. Prox1 deletion in murine dermal lymphatic vessels in vivo and in human LECs increased MMP14 expression. In a hepatocellular carcinoma cell line expressing high endogenous levels of PROX1, its silencing increased both MMP14 expression and MMP14-dependent invasion in 3D. Moreover, PROX1 ectopic expression reduced the MMP14-dependent 3D invasiveness of breast cancer cells and angiogenic sprouting of blood endothelial cells in conjunction with MMP14 suppression. Our study uncovers a new transcriptional regulatory mechanism of cancer cell invasion and endothelial cell specification.

National Category
Cell and Molecular Biology Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-387452 (URN)10.1038/s41598-018-27739-w (DOI)000436046500045 ()29934628 (PubMedID)
Funder
Swedish Research Council, 542-2014-3535The Karolinska Institutet's Research Foundation
Available from: 2019-06-25 Created: 2019-06-25 Last updated: 2019-06-25Bibliographically approved
Gramolelli, S., Cheng, J., Martinez-Corral, I., Vaha-Koskela, M., Elbasani, E., Kaivanto, E., . . . Ojala, P. M. (2018). PROX1 is a transcriptional regulator of MMP14. Scientific Reports, 8, Article ID 9531.
Open this publication in new window or tab >>PROX1 is a transcriptional regulator of MMP14
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2018 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, article id 9531Article in journal (Refereed) Published
Abstract [en]

The transcription factor PROX1 is essential for development and cell fate specification. Its function in cancer is context-dependent since PROX1 has been shown to play both oncogenic and tumour suppressive roles. Here, we show that PROX1 suppresses the transcription of MMP14, a metalloprotease involved in angiogenesis and cancer invasion, by binding and suppressing the activity of MMP14 promoter. Prox1 deletion in murine dermal lymphatic vessels in vivo and in human LECs increased MMP14 expression. In a hepatocellular carcinoma cell line expressing high endogenous levels of PROX1, its silencing increased both MMP14 expression and MMP14-dependent invasion in 3D. Moreover, PROX1 ectopic expression reduced the MMP14-dependent 3D invasiveness of breast cancer cells and angiogenic sprouting of blood endothelial cells in conjunction with MMP14 suppression. Our study uncovers a new transcriptional regulatory mechanism of cancer cell invasion and endothelial cell specification.

Place, publisher, year, edition, pages
Nature Publishing Group, 2018
Keywords
Breast cancer, Cell invasion
National Category
Cell and Molecular Biology Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-386294 (URN)10.1038/s41598-018-27739-w (DOI)000436046500045 ()29934628 (PubMedID)
Funder
Swedish Research Council, 542-2014-3535
Available from: 2019-07-16 Created: 2019-07-16 Last updated: 2019-07-16Bibliographically approved
Zhang, Y., Daubel, N., Stritt, S. & Mäkinen, T. (2018). Transient loss of venous integrity during developmental vascular remodeling leads to red blood cell extravasation and clearance by lymphatic vessels. Development, 145(3), Article ID dev156745.
Open this publication in new window or tab >>Transient loss of venous integrity during developmental vascular remodeling leads to red blood cell extravasation and clearance by lymphatic vessels
2018 (English)In: Development, ISSN 0950-1991, E-ISSN 1477-9129, Vol. 145, no 3, article id dev156745Article in journal (Refereed) Published
Abstract [en]

Maintenance of blood vessel integrity is crucial for vascular homeostasis and is mainly controlled at the level of endothelial cell (EC) junctions. Regulation of endothelial integrity has largely been investigated in the mature quiescent vasculature. Less is known about how integrity is maintained during vascular growth and remodeling involving extensive junctional reorganization. Here, we show that embryonic mesenteric blood vascular remodeling is associated with a transient loss of venous integrity and concomitant extravasation of red blood cells (RBCs), followed by their clearance by the developing lymphatic vessels. In wild-type mouse embryos, we observed activated platelets extending filopodia at sites of inter-EC gaps. In contrast, embryos lacking the activatory C-type lectin domain family 1, member b (CLEC1B) showed extravascular platelets and an excessive number of RBCs associated with and engulfed by the first lymphatic EC clusters that subsequently form lumenized blood-filled vessels connecting to the lymphatic system. These results uncover novel functions of platelets in maintaining venous integrity and lymphatic vessels in clearing extravascular RBCs during developmental remodeling of the mesenteric vasculature. They further provide insight into how vascular abnormalities characterized by blood-filled lymphatic vessels arise.

Place, publisher, year, edition, pages
COMPANY OF BIOLOGISTS LTD, 2018
Keywords
Platelet, Lymphvasculogenesis, Endothelial integrity, Blood-filled lymphatic vessel
National Category
Biological Sciences
Identifiers
urn:nbn:se:uu:diva-347085 (URN)10.1242/dev.156745 (DOI)000424653300006 ()
Funder
EU, European Research Council, ERC-2014-CoG-646849Knut and Alice Wallenberg Foundation, 2015.0030Swedish Research Council, 542-2014-3535German Research Foundation (DFG), STR 1538/1-1
Available from: 2018-03-27 Created: 2018-03-27 Last updated: 2018-08-15Bibliographically approved
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Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0002-9338-1257

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