Výzkum lymfedému, dohledat

Soft matrices

• Induce cell elongation, sprouting and capillary network formation
• Independently of exogenous growth factors
• ECs respond to soft matrix by reduced proliferation !!! [39]
• Factor GATA2 is upregulated on soft matrix [39]

YAP and TAZ

• Key regulators of cell responses to mechanical cues are the
• YAP
• TAZ transcription factors
• Activate targets upon mechanical stimulus
• Stiff ECM
• Stretching
• Shear
• Promote cell proliferation in most cell types, including ECs
• Specific role for TAZ was identified in lymphatic endothelial cells (LECs) in response to oscillatory shear stress (OSS)
• Initiation of luminal valve formation [39]

Oscillatory shear stress - OSS

• Induces LEC quiescence
• Through FOXC2 induction
• Fluid shear stress
• Stiffening of the ECM
• Activate mechanosignalling in the EC [39]

Loss of FOXC2 leads to

• TAZ-dependent cell cycle entry
• Defective valve morphogenesis [39]

• GATA2 transcription factor
• Critical regulator of matrix stiffness
• Induced transcriptional program in the LECs
• Activation of GATA2 by increased mechanical stimulus
• LECs to stiff matrix or oscillatory flow
• GATA2 expression is increased in LECs grown on a soft matrix
• GATA2 is required for early lymphatic vascular morphogenesis
• By controlling lymphangiogenic growth factor responsiveness
• Following the exposure of migrating venous-derived LECs to a soft embryonic tissue [39]

• Venous LEC progenitors experience soft matrix
• Rigid matrices
• Have been shown to support cell–substrate attachment and cell spreading
• Soft matrices
• Promote cell–cell connectivity and endothelial network formation
• Deposition of collagen I
• Predominant collagen type of the ECM
• Contributes to determining tissue stiffness in the embryo
• Arteries and blood capillaries exhibited the highest collagen I density
• CV and the migrating LECs showed moderate or low collagen I [39]

• Soft matrix induced
• Down-regulation of genes encoding regulators of the cell cycle and cell division
• Enrichment of genes encoding molecules involved in cell–matrix adhesion and junctional organization
• Increase in GATA2-regulated expression of genes involved in
• Cell migration
• Vascular development, including
• FLT4/VEGFR332,
• EFNB233,
• ITGA934,
• NOTCH1
• And its targets HEY1 and HEY2 [39]

• Increased GATA2 expression in human primary LECs seeded on soft in comparison to stiff matrix was associated with a concomitant increase in VEGFR3 mRNA expression
• GATA2 regulates VEGFR3 expression in LECs by directly binding to a site in intron 1 of FLT4 [40]