Cooperative ETS transcription factors are required for lymphatic endothelial cell integrity and resilience

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Abstract

Lymphatics maintains fluid homeostasis, immune surveillance, and tissue integrity. Here, we identified the E26 transformation-specific (ETS) transcription factors Erg and Fli1 as essential, cooperative regulators of lymphatic integrity and function. Using inducible, lymphatic endothelial cell-specific deletion in mice, we demonstrated that combined loss of Erg and Fli1 in adults results in fatal lymphatic failure, including chylothorax, chylous ascites, and impaired lymphatic drainage. Single-cell transcriptomic analysis revealed that loss of Erg and Fli1 caused disrupted lymphatic heterogeneity and dysregulation of key lymphatic genes, including valve-specific gene profiles. Erg and Fli1 coordinated lymphatic-immune crosstalk by transcriptionally regulating C-C motif chemokine ligand 21 (Ccl21), which mediates dendritic cell trafficking. Their loss also induced pro-inflammatory and pro-thrombotic gene expression, further contributing to lymphatic dysfunction. During embryonic development, the co-deletion led to lymphatic mis-patterning and loss of valve-initiating lymphatic endothelial cell clusters. The impact of loss of Erg and Fli1 function on lymphatic development in mice is consistent with FOXC2 mutations in lymphedema-distichiasis syndrome or ERG gene variants underlying primary lymphoedema in humans. Moreover, Erg and Fli1 were required for regenerative lymphangiogenesis and lymphatic repair following injury in adults. Our findings establish Erg and Fli1 as core transcriptional regulators of lymphatic identity, integrity, and function.

Authors

Myung Jin Yang, Seok Kang, Seon Pyo Hong, Hokyung Jin, Jin-Hui Yoon, Cheolhwa Jin, Chae Min Yuk, Lidiya G Gebeyehu, Junho Jung, Sung-hwan Yoon, Hyuek jong Lee, Gou Young Koh