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

Maike Frye, Andrea Taddei, Cathrin Dierkes, Ines Martinez-Corral, Matthew Fielden, Henrik Ortsäter, Jan Kazenwadel, Dinis P. Calado, Pia Ostergaard, Marjo Salminen, Liqun He, Natasha L. Harvey, Friedemann Kiefer and Taija Mäkinen ()
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Maike Frye: Uppsala University
Andrea Taddei: The Francis Crick Institute
Cathrin Dierkes: Max Planck Institute for Molecular Biomedicine
Ines Martinez-Corral: Uppsala University
Matthew Fielden: Albanova University Center
Henrik Ortsäter: Uppsala University
Jan Kazenwadel: University of South Australia and SA Pathology
Dinis P. Calado: The Francis Crick Institute
Pia Ostergaard: St George’s University of London
Marjo Salminen: University of Helsinki
Liqun He: Tianjin Medical University General Hospital
Natasha L. Harvey: University of South Australia and SA Pathology
Friedemann Kiefer: Max Planck Institute for Molecular Biomedicine
Taija Mäkinen: Uppsala University

Nature Communications, 2018, vol. 9, issue 1, 1-16

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-03959-6

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