Mapping vascular plasticity during fibrogenesis identifies fibrosis-associated endothelial cells in early-stage liver disease

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Abstract

Vascular plasticity is a crucial biological asset enabling our bodies to rapidly adapt to infections and acute inflammation. However, repeated insults during chronic disease can result in these vascular adaptations becoming irreversible, thereby driving disease progression and fibrosis. This study aimed to understand if phenotypic changes in endothelial cell (EC) identity could be indicative of progressive fibrosis and thereby offer diagnostic and therapeutic opportunities for patients with metabolic dysfunction-associated steatotic liver disease (MASLD). We integrated high-resolution imaging, proteomic and transcriptomic analysis which collectively highlighted a central role for endothelial-to-mesenchymal transition (EndMT)-induced EC plasticity in the derivation of ‘fibrosis-associated’ EC (FAEC). We demonstrated that: 1) full spectrum flow cytometry can provide new opportunities to categorize and phenotype EC subpopulations, 2) two distinct EndMT-derived FAEC subpopulations expanded during fibrogenesis; THY1.2+ICAM1+ and TAGLN+MCAM+ EC that displayed unique immunomodulatory and metabolic phenotypes, 3) TAGLN+ FAEC are a conserved, pro-fibrotic cell type that arose at early stages of MASLD, and 4) increased hepatic expression of TAGLN was significantly associated with detrimental patient outcomes at all stages of liver disease. This study paves the way for the development of FAEC-specific diagnostic and therapeutic approaches to tackle progressive fibrotic disease.

Authors

Christina Gkantsinikoudi, Joshua P. Dignam, Raju Kumar, Elliot Jokl, Meenakshi Rana, Wenhao Li, Maryna Samus, Stephanie Landi, Varinder S. Athwal, Timothy J. Kendall, Antal Rot, Jonathan A. Fallowfield, Karen Piper Hanley, William Alazawi, Neil P. Dufton