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20351309
An exquisite cross-control mechanism among endothelial cell fate regulators directs the plasticity and heterogeneity of lymphatic endothelial cells.

Blood, 2010/7/08;116(1):140-50.

Kang J[1], Yoo J, Lee S, Tang W, Aguilar B, Ramu S, Choi I, Otu HH, Shin JW, Dotto GP, Koh CJ, Detmar M, Hong YK

Affiliations

PMID: 20351309DOI: 10.1182/blood-2009-11-252270

Impact factor: 25.476

Abstract
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.
MeSH terms
Adaptor Proteins, Signal Transducing; Basic Helix-Loop-Helix Transcription Factors; Blotting, Western; COUP Transcription Factor II; Calcium-Binding Proteins; Cell Cycle Proteins; Cell Differentiation; Cells, Cultured; Down-Regulation; Endothelial Cells; Feedback, Physiological; Gene Expression Profiling; Homeodomain Proteins; Humans; Intercellular Signaling Peptides and Proteins; Membrane Proteins; Models, Biological; Oligonucleotide Array Sequence Analysis; Protein Binding; RNA Interference; Receptor, Notch1; Repressor Proteins; Reverse Transcriptase Polymerase Chain Reaction; Serrate-Jagged Proteins; Signal Transduction; Tumor Suppressor Proteins
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