Single-cell and spatial atlas of human and mouse trisomy 21 hearts

About This Grant

Down syndrome is the most common genetic disorder that is primarily caused by an additional copy of human chromosome 21, trisomy 21 (T21). DS occurs in 16 per 10,000 live births, and is characterized by distinct facial appearance, intellectual disability, and developmental delays. A spectrum of co-occurring conditions are present in subjects with DS, with about half born with congenital heart defects (CHDs). Common CHDs in DS include atrial septal defects, ventricular septal defects, and atrioventricular septal defects. Genetically engineered mouse models including Dp1Tyb (triplication of MMU16) and TcMAC21 (transchromosomic Hsa21) mouse lines have been created to recapitulate CHDs in DS, with high penetrance of cardiac structural defects in septum and valve abnormalities. In parallel, DS patient-specific induced pluripotent stem cells (iPSCs) are versatile in vitro models with complete genetic content of T21 of affected patients. Human iPSC-derived compartment-specific cardioids including atrioventricular canal (AVC)-like cardioids may precisely mimic cell lineage architecture of the human heart and recapitulate septal defects in DS. While progress has been towards understanding clinical features of CHD in DS, underlying mechanisms by which T21 contributes to early cardiac cell lineage differentiation and septal defects are still not fully revealed. In response to this FOA PAR-22-247, we aim to establish a single-cell and spatial atlas of T21 hearts using both DS mouse model and patient-specific iPSCs to understand how T21 disrupts cardiac cell lineage differentiation. By leveraging in vivo Dp1Tyb/TcMAC21 mouse models and in vitro patient-specific iPSCs as well as cutting-edge single-cell and spatial transcriptomics, the overarching goal of this R24 project is to elucidate cellular and tissue mechanisms of septal defects in DS by deep phenotyping of DS iPSC-derived AVC-like cardioids and T21 mouse embryonic hearts at single-cell and spatial resolution. In Aim 1, we will determine in vitro mechanisms by which T21 leads to abnormal cardiac cell lineage differentiation and septal defects by single-cell and spatial transcriptomic analysis of DS iPSC-derived AVC-like cardioids. In Aim 2, we will interrogate in vivo etiologies of abnormal early cardiac cell development and septal formation in DS by single-cell and spatial transcriptomic analysis of mouse T21 hearts. In Aim 3, we will construct and disseminate single-cell and spatial atlas of human and mouse T21 hearts for open access through the INCLUDE Experimental Models of Down Syndrome (EMODS) portal. This R24 project will create a single-cell and spatial atlas of human and mouse T21 hearts that will be valuable resource for understanding how T21 leads to CHDs in DS using both mouse model and human iPSC-derived cardioids.