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

Jinjoo Kang, Jaehyuk Yoo, Sunju Lee, Wanli Tang, Berenice Aguilar, Swapnika Ramu, Inho Choi, Hasan H. Otu, Jay W. Shin, G. Paolo Dotto, Chester J. Koh, Michael Detmar, Young Kwon Hong

Research output: Contribution to journalArticle

60 Scopus citations

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 coreside 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 COUPTFII 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.

Original languageEnglish (US)
Pages (from-to)140-150
Number of pages11
JournalBlood
Volume116
Issue number1
DOIs
StatePublished - Jul 8 2010

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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    Kang, J., Yoo, J., Lee, S., Tang, W., Aguilar, B., Ramu, S., Choi, I., Otu, H. H., Shin, J. W., Dotto, G. P., Koh, C. J., Detmar, M., & Hong, Y. K. (2010). An exquisite cross-control mechanism among endothelial cell fate regulators directs the plasticity and heterogeneity of lymphatic endothelial cells. Blood, 116(1), 140-150. https://doi.org/10.1182/blood-2009-11-252270