Authors
Xiaoyuan Zhang, Lun Zhu, Ze Sun, Ruolin Jia, Ziming Wang, Jiayao Zhao, Bohao Liu, Haiqing Xiong, Xiaowei Yu, Yanzhu Yue
Published in
Advanced science (Weinheim, Baden-Wurttemberg, Germany). Pages e78016. Sep 27, 2026. Epub Sep 27, 2026.
Abstract
Precise extracellular matrix (ECM) coordination is essential for cardiac septation, yet the molecular etiology of human isolated perimembranous ventricular septal defects (VSD) remains elusive. Here, we constructed a high-resolution single-cell transcriptomic atlas of human VSD, benchmarking the pathological state against a 7-22 week developmental trajectory. Integrating these single-cell profiles with a reference-based spatial transcriptomic map, we deconvolved the distinct molecular signatures of membranous and muscular septal regions. We found that aberrant cardiomyocyte hypertrophy operates alongside a systemic failure in the non-myocyte microenvironment. Crucially, the ECM regulatory network is dysregulated, driven by attenuated endothelial-fibroblast crosstalk and downregulated THBS1-integrin signaling. Supported by in vitro assays, this dysregulation impairs key endothelial-to-mesenchymal transition (EndoMT) programs and transcriptionally suppresses MMP2. Spatial reconstruction confirmed this maturation block compromises both septal regions, indicating a global remodeling arrest that precludes physical closure. Validated by in situ immunofluorescence and a robust correlation between reduced maternal serum MMP2 levels and defect size, our study portrays VSD as a disease driven by microenvironmental insufficiency and arrested remodeling, providing an integrative framework for understanding human cardiac dysmorphogenesis.
PMID:
42801549
Bibliographic data and abstract were imported from PubMed on 28 Sep 2026.
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