Human Cardiac Organoids Reveal HAND1 Loss-Associated Alterations in Cell Composition During Early Cardiac Differentiation
4 affiliations
- 1School of Pharmaceutical Sciences, Fudan University, Shanghai 201203, China
- 2China State Institute of Pharmaceutical Industry Co., Ltd., Shanghai 201203, China
- 3Shanghai InnoStar Bio-Tech Co., Ltd., Shanghai 201203, China
- 4Innovation Center for AI and Drug Discovery, School of Pharmacy, East China Normal University, Shanghai 200062, China
Abstract
Understanding early cardiac developmental abnormalities requires linking tissue phenotypes to the cellular populations produced during differentiation. We established a cardiac organoid platform derived from human induced pluripotent stem cells (hiPSCs) and combined phenotypic assays, time-course and day-9 single-cell transcriptomics, and cleavage under targets and tagmentation (CUT&Tag) to investigate developmental perturbations. Organoids contained multiple cell populations and exhibited stage-dependent cardiac transcriptional programs. Thalidomide exposure altered morphology and reduced TNNT2-positive tissue area, with lower calcium transient amplitude at 0.01 μg/mL. RNA sequencing at 10 μg/mL identified downregulation of heart and neural crest derivatives expressed 1 (HAND1), prompting a separate genetic investigation. Across three paired differentiation experiments using one characterized HAND1-knockout clone, reduced cardiomyocyte representation accompanied relative enrichment of mesodermal/mesenchymal-like cells. Selected cardiac-associated expression abnormalities persisted at day 15. Expression and chromatin occupancy analyses identified candidate regulatory associations, with locus-specific quantitative PCR supporting HAND1 occupancy at selected cardiac-associated regions. Independent genetic and functional validation is needed to test causal relationships. Together, these findings place HAND1 loss-associated tissue abnormalities in their cellular context and identify candidate occupied regions for investigating early cardiac differentiation in a human three-dimensional model.
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BibTeX
@article{yang2026human,
title = {{Human Cardiac Organoids Reveal HAND1 Loss-Associated Alterations in Cell Composition During Early Cardiac Differentiation}},
author = {Hao Yang and Yunqian Zeng and Yiyang Teng and Qi Zhao and Minbo Hou and Zhikai Cheng and Xuemei Zhang and Xijie Wang},
journal = {Cells},
year = {2026},
month = oct,
doi = {10.3390/cells15211948},
url = {https://www.mdpi.com/2073-4409/15/21/1948},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Human Cardiac Organoids Reveal HAND1 Loss-Associated Alterations in Cell Composition During Early Cardiac Differentiation
AU - Hao Yang
AU - Yunqian Zeng
AU - Yiyang Teng
AU - Qi Zhao
AU - Minbo Hou
AU - Zhikai Cheng
AU - Xuemei Zhang
AU - Xijie Wang
PY - 2026
DA - 2026/10/26
JO - Cells
DO - 10.3390/cells15211948
UR - https://www.mdpi.com/2073-4409/15/21/1948
AB - Understanding early cardiac developmental abnormalities requires linking tissue phenotypes to the cellular populations produced during differentiation. We established a cardiac organoid platform derived from human induced pluripotent stem cells (hiPSCs) and combined phenotypic assays, time-course and day-9 single-cell transcriptomics, and cleavage under targets and tagmentation (CUT&Tag) to investigate developmental perturbations. Organoids contained multiple cell populations and exhibited stage-dependent cardiac transcriptional programs. Thalidomide exposure altered morphology and reduced TNNT2-positive tissue area, with lower calcium transient amplitude at 0.01 μg/mL. RNA sequencing at 10 μg/mL identified downregulation of heart and neural crest derivatives expressed 1 (HAND1), prompting a separate genetic investigation. Across three paired differentiation experiments using one characterized HAND1-knockout clone, reduced cardiomyocyte representation accompanied relative enrichment of mesodermal/mesenchymal-like cells. Selected cardiac-associated expression abnormalities persisted at day 15. Expression and chromatin occupancy analyses identified candidate regulatory associations, with locus-specific quantitative PCR supporting HAND1 occupancy at selected cardiac-associated regions. Independent genetic and functional validation is needed to test causal relationships. Together, these findings place HAND1 loss-associated tissue abnormalities in their cellular context and identify candidate occupied regions for investigating early cardiac differentiation in a human three-dimensional model.
SN - 2073-4409
ER -