4D-CARDIOSPACE
4D Spatiotemporal Multiomic Analyses Reveal Morphogenetic Mechanisms Forming the Early Mammalian Heart
The heart is the first organ to form, and disruption in its morphogenesis underlies congenital heart disease, the most common birth defect. This project combines MERFISH imaging, 3D reconstruction, and single-cell multi-omics to build a four-dimensional cell atlas of cardiac embryogenesis, mapping spatial organization, lineage heterogeneity, migratory trajectories, regulatory programs, and signaling mechanisms that shape early mammalian heart formation.
Summary
Spatial mechanisms of heart morphogenesis
We combined MERFISH imaging, 3D reconstruction, and single-cell multi-omics to build a four-dimensional cell atlas of cardiac embryogenesis, 4D-CARDIOSPACE, mapping the spatial organization and dynamic heterogeneity of cardiac cell populations across key developmental stages and precisely tracking their migratory trajectories.
Integrating spatial cell-cell interaction modeling with regulatory network analysis revealed an unrecognized role for canonical Wnt/β-catenin signaling. Beyond specifying cardiac progenitors, spatially differential Wnt/β-catenin activity drives regional progenitor migration by regulating epithelial-to-mesenchymal transition. Cardiogenic mesoderm-specific Wnt/β-catenin knockout mice displayed disrupted progenitor organization and impaired heart tube formation.
Highlights
Key findings
- A 4D single-cell spatial atlas resolves approximately 900,000 cells across 84 populations during mouse cardiogenesis from gastrulation to four-chamber morphogenesis.
- Three major heart field progenitor populations occupy spatially segregated, reproducible 3D domains arranged around a cavity structure before overt heart morphogenesis.
- Spatially organized canonical Wnt, FGF, and RA gradients, together with progenitor-specific gene regulatory networks, coordinate cardiac lineage specification and morphogenetic cell behaviors.
- A spatially graded epithelial-to-mesenchymal transition program renders first heart field/juxtacardiac field progenitors highly motile while maintaining second heart field progenitors as a constrained epithelial reservoir.
- Canonical Wnt/β-catenin signaling, driven by Wnt2/Wnt6 from neighboring tissues, regulates the FHF/JCF EMT program and is required for cardiogenic mesoderm folding and heart tube formation.
Keywords
Affiliations
- Department of Medicine, Division of Cardiology, University of California San Diego, La Jolla, CA, USA
- Department of Genetics, Stanford University, Stanford, CA, USA
- Basic Sciences and Engineering Initiative, Betty Irene Moore Children's Heart Center, Lucile Packard Children's Hospital, Stanford University, Stanford, CA, USA
- Department of Computer Science, Stanford University, Stanford, CA, USA
- Stanford Cardiovascular Institute, Stanford University, Stanford, CA, USA
- Bioinformatics and Systems Biology Graduate Program, University of California San Diego, La Jolla, CA, USA
- Bioengineering Graduate Program, University of California San Diego, La Jolla, CA, USA
- Infrastructure Solution Group, Lenovo
- Skaggs School of Pharmacy and Pharmaceutical Sciences, Department of Pharmacology, School of Medicine, University of California San Diego, La Jolla, CA, USA
- Institute for Genomic Medicine, School of Medicine, University of California San Diego, La Jolla, CA, USA
- Institute of Engineering in Medicine, University of California San Diego, La Jolla, CA, USA