ArticleAdvanced science (Weinheim, Baden-Wurttemberg, Germany)2026
A Spatiotemporal Single-Cell Atlas Uncovers Dysregulated ECM Dynamics and Septal Remodeling Arrest in Human Ventricular Septal Defects.
Xiaoyuan Zhang, Lun Zhu, Ze Sun, Ruolin Jia, Ziming Wang, Jiayao Zhao, Bohao Liu, Haiqing Xiong, Xiaowei Yu, Yanzhu Yue
Abstract read
In one paragraphArticle in Advanced science (Weinheim, Baden-Wurttemberg, Germany), 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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5 · Who and what moneyAuthors and funding
10 authors.
Xiaoyuan Zhang *Prenatal Diagnosis Center, Reproductive Medicine Center, Department of Cell Fate and Diseases, Jilin Provincial Key Laboratory of Women's Reproductive Health, Jilin Provincial Clinical Research Center for Birth Defect and Rare Disease, The First Hospital of Jilin University, Changchun, Jilin, China.
Lun Zhu *Prenatal Diagnosis Center, Reproductive Medicine Center, Department of Cell Fate and Diseases, Jilin Provincial Key Laboratory of Women's Reproductive Health, Jilin Provincial Clinical Research Center for Birth Defect and Rare Disease, The First Hospital of Jilin University, Changchun, Jilin, China.ORCID https://orcid.org/0009-0005-2682-2250 Ze SunPrenatal Diagnosis Center, Reproductive Medicine Center, Department of Cell Fate and Diseases, Jilin Provincial Key Laboratory of Women's Reproductive Health, Jilin Provincial Clinical Research Center for Birth Defect and Rare Disease, The First Hospital of Jilin University, Changchun, Jilin, China.
Ziming WangPrenatal Diagnosis Center, Reproductive Medicine Center, Department of Cell Fate and Diseases, Jilin Provincial Key Laboratory of Women's Reproductive Health, Jilin Provincial Clinical Research Center for Birth Defect and Rare Disease, The First Hospital of Jilin University, Changchun, Jilin, China.
Jiayao ZhaoPrenatal Diagnosis Center, Reproductive Medicine Center, Department of Cell Fate and Diseases, Jilin Provincial Key Laboratory of Women's Reproductive Health, Jilin Provincial Clinical Research Center for Birth Defect and Rare Disease, The First Hospital of Jilin University, Changchun, Jilin, China.
Bohao LiuPrenatal Diagnosis Center, Reproductive Medicine Center, Department of Cell Fate and Diseases, Jilin Provincial Key Laboratory of Women's Reproductive Health, Jilin Provincial Clinical Research Center for Birth Defect and Rare Disease, The First Hospital of Jilin University, Changchun, Jilin, China.ORCID https://orcid.org/0000-0002-1070-1308 Haiqing XiongState Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China.
Yanzhu YuePrenatal Diagnosis Center, Reproductive Medicine Center, Department of Cell Fate and Diseases, Jilin Provincial Key Laboratory of Women's Reproductive Health, Jilin Provincial Clinical Research Center for Birth Defect and Rare Disease, The First Hospital of Jilin University, Changchun, Jilin, China.ORCID https://orcid.org/0000-0002-6287-3398 Funding
Bethune Medical Department of Jilin University 4044450001Bethune Medical Department of Jilin University 4047330002CAMS Innovation Fund for Medical Sciences (CIFMS) 2022-I2M-1-022CAMS Innovation Fund for Medical Sciences (CIFMS) 2023-I2M-2-007CAMS Innovation Fund for Medical Sciences (CIFMS) 2025-I2M-XHXX-138Fundamental Research Funds for the Central Universities, JLU 419021425Y11Jilin Provincial Department of Science and Technology YDZJ202501ZYTS726National Key R&D Program of China 2022YFA1106200National Natural Science Foundation of China 32370873National Natural Science Foundation of China 32522028Natural Science Foundation of Jilin Province 20250101028JJNon-profit Central Research Institute Fund of Chinese Academy of Medical Sciences 2022-RC180-07The National Natural Science Foundation of China 32470884
6 · The paper itselfAbstract
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.
Indexed as
extracellular matrix remodelingheart developmentmicroenvironmental insufficiencyMMP2 (matrix metalloproteinase 2)ventricular septal defect
Identifiers
PMID42801549
PMCPMC13616362
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