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Nat Commun. 2018 Apr 17;9(1):1511. doi: 10.1038/s41467-018-03959-6.

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

Author information

1
Department of Immunology, Genetics and Pathology, Uppsala University, Dag Hammarskjölds väg 20, 751 85, Uppsala, Sweden.
2
Immunity and Cancer Laboratory, The Francis Crick Institute, 1 Midland Road, NW11AT, London, UK.
3
Max Planck Institute for Molecular Biomedicine, 48149, Münster, Germany.
4
Department of Applied Physics, KTH Royal Institute of Technology, Albanova University Center, 106 91, Stockholm, Sweden.
5
Centre for Cancer Biology, University of South Australia and SA Pathology, SA5000, Adelaide, South Australia, Australia.
6
Lymphovascular Research Unit, Molecular and Clinical Sciences Institute, St George's University of London, SW170RE, London, UK.
7
Department of Veterinary Biosciences, University of Helsinki, 00014, Helsinki, Finland.
8
Department of Neurosurgery, Tianjin Neurological Institute, Key Laboratory of Post-Neuroinjury Neuro-Repair and Regeneration in Central Nervous System, Ministry of Education and Tianjin City, Tianjin Medical University General Hospital, Tianjin, 300052, China.
9
European Institute for Molecular Imaging (EIMI), University of Münster, Waldeyerstr. 15, 48149, Münster, Germany.
10
Department of Immunology, Genetics and Pathology, Uppsala University, Dag Hammarskjölds väg 20, 751 85, Uppsala, Sweden. taija.makinen@igp.uu.se.

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.

PMID:
29666442
PMCID:
PMC5904183
DOI:
10.1038/s41467-018-03959-6
[Indexed for MEDLINE]
Free PMC Article

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