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Matrix stiffness controls lymphatic vessel formation through regulation of a GATA2-dependent transcriptional program.

Frye, M; Taddei, A; Dierkes, C; Martinez-Corral, I; Fielden, M; Ortsäter, H; Kazenwadel, J; Calado, DP; Ostergaard, P; Salminen, M; et al. Frye, M; Taddei, A; Dierkes, C; Martinez-Corral, I; Fielden, M; Ortsäter, H; Kazenwadel, J; Calado, DP; Ostergaard, P; Salminen, M; He, L; Harvey, NL; Kiefer, F; Mäkinen, T (2018) Matrix stiffness controls lymphatic vessel formation through regulation of a GATA2-dependent transcriptional program. Nat Commun, 9 (1). p. 1511. ISSN 2041-1723 https://doi.org/10.1038/s41467-018-03959-6
SGUL Authors: Ostergaard, Pia

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Abstract

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.

Item Type: Article
Additional Information: This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. © The Author(s) 2018
Keywords: MD Multidisciplinary
SGUL Research Institute / Research Centre: Academic Structure > Molecular and Clinical Sciences Research Institute (MCS)
Journal or Publication Title: Nat Commun
ISSN: 2041-1723
Language: eng
Dates:
DateEvent
17 April 2018Published
22 March 2018Accepted
Publisher License: Creative Commons: Attribution 4.0
Projects:
Project IDFunderFunder ID
646849European Research Councilhttp://dx.doi.org/10.13039/501100000781
D0368601Swedish Research CouncilUNSPECIFIED
542-2014-3535Swedish Research CouncilUNSPECIFIED
CAN 2013/387Swedish Cancer SocietyUNSPECIFIED
FC001057Cancer Research UKhttp://dx.doi.org/10.13039/501100000289
FC001057Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
FC001057Wellcome Trusthttp://dx.doi.org/10.13039/100004440
SP/13/5/30288British Heart Foundationhttp://dx.doi.org/10.13039/501100000274
APP1061365Australian Government National Health and Medical Research CouncilUNSPECIFIED
PubMed ID: 29666442
Web of Science ID: WOS:000430196200006
Go to PubMed abstract
URI: http://sgultest.da.ulcc.ac.uk/id/eprint/109820
Publisher's version: https://doi.org/10.1038/s41467-018-03959-6

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