한빛사논문
- 조회1,320
Siyeon Rhee1,†, David T. Paik2,3,4,†, Johnson Y. Yang2,3,4, Danielle Nagelberg1, Ian Williams1,2, Lei Tian2,3,4, Robert Roth1, Mark Chandy2,3,4, Jiyeon Ban1, Nadjet Belbachir2,3,4, Seokho Kim5, Hao Zhang2,3,4, Ragini Phansalkar6, Ka Man Wong1, Devin A. King1, Caroline Valdez1, Virginia D. Winn7, Ashby J. Morrison1,*, Joseph C. Wu2,3,4,*, and Kristy Red-Horse1,2,4,*
1Department of Biology, Stanford University, Stanford, CA 94305, USA; 2Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305, USA; 3
Department of Medicine, Division of Cardiology, Stanford University School of Medicine, Stanford University, Stanford, CA, USA; 4Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA; 5Department of Developmental Biology, Stanford University School of Medicine, Stanford University, Stanford, CA 94305, USA; 6Department of Genetics, Stanford University School of Medicine, Stanford University, Stanford, CA 94305, USA; and 7Department of Obstetrics and Gynecology, Stanford University School of Medicine, Stanford University, Stanford, CA 94305, USA
*Corresponding authors.
†These authors contributed equally to this work
Abstract
Aims
Non-compaction cardiomyopathy is a devastating genetic disease caused by insufficient consolidation of ventricular wall muscle that can result in inadequate cardiac performance. Despite being the third most common cardiomyopathy, the mechanisms underlying the disease, including the cell types involved, are poorly understood. We have previously shown that endothelial cell-specific deletion of the chromatin remodeller gene Ino80 results in defective coronary vessel development that leads to ventricular non-compaction in embryonic mouse hearts. We aimed to identify candidate angiocrines expressed by endocardial and ECs inwildtype and LVNC conditions in Tie2Cre;Ino80fl/fl transgenic embryonic mouse hearts, and test the effect of these candidates on cardiomyocyte proliferation and maturation.
Methods and results
We used single-cell RNA-sequencing to characterize endothelial and endocardial defects in Ino80-deficient hearts. We observed a pathological endocardial cell population in the non-compacted hearts and identified multiple dysregulated angiocrine factors that dramatically affected cardiomyocyte behaviour. We identified Col15A1 as a coronary vessel-secreted angiocrine factor, downregulated by Ino80-deficiency, that functioned to promote cardiomyocyte proliferation. Furthermore, mutant endocardial and endothelial cells (ECs) up-regulated expression of secreted factors, such as Tgfbi, Igfbp3, Isg15, and Adm, which decreased cardiomyocyte proliferation and increased maturation.
Conclusions
These findings support a model where coronary ECs normally promote myocardial compaction through secreted factors, but that endocardial and ECs can secrete factors that contribute to non-compaction under pathological conditions.
논문정보
- Research article
- 2021년 07월 (BRIC 등록일 2021-10-25)
- 국외 연구진
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