Spatial and Single-Nucleus Multiomics Profiling Reveals Heterogeneous Endothelial Cell Overabundance in Endocardial Fibroelastosis

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Endocardial fibroelastosis in hypoplastic left heart syndrome is driven by an overabundance of dysregulated, pro-fibrotic endothelial cell subpopulations rather than fibroblast expansion. Novelty: ClaimNovelty.NOVEL_FINDING. Consensus alignment: ConsensusAlignment.CHALLENGES_CONSENSUS.

Yang Yu; Gaopeng Xian; Shaila Saifee; Michael A. Trembley; A. Kulandaisamy; Yanqiang Li; Shenli Yuan; Min Chen; Yapeng Liu; Jiehui Chen; Yunxia Wang; Yi Wang; Rongbin Zheng; Xinlei Gao; Dean Li; Jiayi Chen; Ingeborg Friehs; Pedro J. del Nido; Stephen P. Sanders; Chrystalle Katte Carreon; William T. Pu; Kaifu Chen; Lili Zhang

doi:10.1161/circulationaha.125.077386

Key Points

To characterize the cellular landscape and investigate the pathogenic role of endothelial cells in endocardial fibroelastosis associated with hypoplastic left heart syndrome.
Applied multiplexed error-robust fluorescence in situ hybridization (MERFISH) on 2 additional endocardial fibroelastosis samples and 3 controls (total disease cohort n=5).
Functionally validated disease-associated signaling pathways in vitro using human microvascular endothelial cells and smooth muscle cell co-cultures.
Revealed marked enrichment of endothelial cells rather than fibroblasts in endocardial fibroelastosis, uncovering two distinct disease-specific subpopulations (EC_2 and EC_3) with elevated pro-fibrotic gene expression (COL1A1) and reduced endothelial identity (PECAM1).
Demonstrated that EC_3 acquires mesenchymal and fibroblast markers (DCN) through endothelial-to-mesenchymal transition, whereas EC_2 undergoes muscle-like reprogramming marked by MEF2D and TNNT2 expression alongside sprouting angiogenesis enrichment.
Identified hyperactivation of cardiomyocyte-to-endothelial SEMA3C, VEGFA, and FGF1 signaling with increased FLI1 occupancy, while MERFISH showed spatial colocalization of abnormal endothelial cells with smooth muscle cells.

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Implication

Single-nucleus multiomic profiling reveals heterogeneous endothelial cell expansion in endocardial fibroelastosis, indicating a non-fibroblast mechanism of cardiac fibrosis.

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Cite This Study

Yu et al. (2026) studied this question.

synapsesocial.com/papers/6a8ebc26451774b83f3b4d38 https://doi.org/10.1161/circulationaha.125.077386

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Spatial and Single-Nucleus Multiomics Profiling Reveals Heterogeneous Endothelial Cell Overabundance in Endocardial Fibroelastosis

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Spatial and Single-Nucleus Multiomics Profiling Reveals Heterogeneous Endothelial Cell Overabundance in Endocardial Fibroelastosis

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