Developmental dynamics of cardiac progenitors and their role in congenital heart defects

Abstract: Cardiac progenitors are the fundamental building blocks of the heart and play a central role in the pathogenesis of congenital heart defects. Recent single-cell RNA sequencing studies have revealed that the cell populations in both developing and mature heart are more diverse than previously recognized. In particular, there has been a great interest in characterizing the transcriptional signatures of human cardiac progenitor populations and building a roadmap of the early heart lineages. This thesis work is a part of an ongoing effort to map the early human heart progenitors, their developmental dynamics and their role in the pathogenesis of congenital heart defects at a single-cell resolution. In paper I, we present a single-cell characterization of in vitro cardiac differentiation of human embryonic stem cells to beating cardiomyocytes and other populations. We used single-cell RNA sequencing data integration to compare the in vitro-derived cardiac cells to human embryonic heart, studied the developmental dynamics of cardiac progenitors by building a differentiation roadmap, and investigated the effect of loss of ISL1 transcription factor on the differentiation process. In paper II, we mapped the genetic landscape of non-syndromic Tetralogy of Fallot, a form of complex congenital heart defect, in a cohort of 146 patient-parent trios. We intersected the identified disease-associated genes with single-cell RNA sequencing analysis of in vivo and in vitro human cardiac development generated by us and other laboratories. Interestingly, we could pinpoint cardiac progenitors as a cellular hotspot in cardiac disease pathogenesis. Paper III introduces a novel cardiac progenitor marked by LGR5, which exists both in the human embryonic heart in vivo and the human embryonic stem cell cardiac differentiation system in vitro. The LGR5+ cono-ventricular progenitor population originates from the ISL1+ progenitor pool and populates the cardiac outflow tract, a cardiac region often affected in congenital heart defects. Taken together, these studies support the importance of cardiac progenitors in the pathogenesis of cardiac abnormalities and explore their developmental dynamics at a singlecell level.

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