Article: article from journal or magazin.
An exquisite cross-control mechanism among endothelial cell fate regulators directs the plasticity and heterogeneity of lymphatic endothelial cells.
Arteriovenous-lymphatic endothelial cell fates are specified by the master regulators, namely, Notch, COUP-TFII, and Prox1. Whereas Notch is expressed in the arteries and COUP-TFII in the veins, the lymphatics express all 3 cell fate regulators. Previous studies show that lymphatic endothelial cell (LEC) fate is highly plastic and reversible, raising a new concept that all 3 endothelial cell fates may co-reside in LECs and a subtle alteration can result in a reprogramming of LEC fate. We provide a molecular basis verifying this concept by identifying a cross-control mechanism among these cell fate regulators. We found that Notch signal down-regulates Prox1 and COUP-TFII through Hey1 and Hey2 and that activated Notch receptor suppresses the lymphatic phenotypes and induces the arterial cell fate. On the contrary, Prox1 and COUP-TFII attenuate vascular endothelial growth factor signaling, known to induce Notch, by repressing vascular endothelial growth factor receptor-2 and neuropilin-1. We show that previously reported podoplanin-based LEC heterogeneity is associated with differential expression of Notch1 in human cutaneous lymphatics. We propose that the expression of the 3 cell fate regulators is controlled by an exquisite feedback mechanism working in LECs and that LEC fate is a consequence of the Prox1-directed lymphatic equilibrium among the cell fate regulators.
Basic Helix-Loop-Helix Transcription Factors/genetics, Basic Helix-Loop-Helix Transcription Factors/metabolism, Blotting, Western, COUP Transcription Factor II/genetics, COUP Transcription Factor II/metabolism, Calcium-Binding Proteins/genetics, Calcium-Binding Proteins/metabolism, Cell Cycle Proteins/genetics, Cell Cycle Proteins/metabolism, Cell Differentiation, Cells, Cultured, Down-Regulation, Endothelial Cells/cytology, Endothelial Cells/metabolism, Feedback, Physiological, Gene Expression Profiling, Homeodomain Proteins/genetics, Homeodomain Proteins/metabolism, Humans, Intercellular Signaling Peptides and Proteins/genetics, Intercellular Signaling Peptides and Proteins/metabolism, Membrane Proteins/genetics, Membrane Proteins/metabolism, Models, Biological, Oligonucleotide Array Sequence Analysis, Protein Binding, RNA Interference, Receptor, Notch1/genetics, Receptor, Notch1/metabolism, Repressor Proteins/genetics, Repressor Proteins/metabolism, Reverse Transcriptase Polymerase Chain Reaction, Signal Transduction, Tumor Suppressor Proteins/genetics, Tumor Suppressor Proteins/metabolism
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