The gene regulatory networks underlying early human cardiovascular (CV) development is poorly understood, in large part due to the dearth of molecular and genetic information specifying the diversity of cardiovascular progenitor cell-types (CVPCs). Human pluripotent stem cell (hPSC)-derived CV cells provide a model for human cardiogenesis and afford us the opportunity to reveal the various CV cell types generated during heart development and to also functionally discover and validate CV developmental gene regulatory networks. In this proposal, we will employ single cell transcriptome (RNA-seq) analysis to dissect the heterogeneity of early CV progenitor populations that give rise to the spectrum of distinct CV cell types and their intermediates. By identifying these potentially rare and novel progenitor cell types as well as studying their lineage choice decisions at the single cell level, the cellular and molecular networks underlying these progenitor cells and their differentiated CV cell types that control their differentiation can be revealed. To achieve our goal, a synergistic and complementary collaboration between the Yeo and Chi labs will aim to (1) investigate the diversity and organization of CV cellular subtypes during cardiogenesis in vitro, (2) develop novel algorithms that enable the extraction of gene regulatory programs that specify CV lineage sub-networks and (3) investigate the functional significance of identified CV cell subtypes. If successful, we will reveal pathways and cell-types that will advance our basic and translational framework for treating congenital heart disease.

Public Health Relevance

This proposal seeks to develop network-based algorithms to perform single-cell transcriptome analysis during derivation of cardiovascular progenitor cells from engineered human pluripotent stem cells to extract previously unknown subpopulations of cardiovascular cell-types and gene regulatory networks underlying cardiovascular lineage specification. These basic and translational studies will provide novel insights into human heart development as well as innovative strategies for developing future treatments for congenital heart disease, which accounts for a third of all major congenital anomalies.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Fehr, Tuba Halise
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University of California, San Diego
Other Basic Sciences
Schools of Medicine
La Jolla
United States
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van den Hurk, Mark; Erwin, Jennifer A; Yeo, Gene W et al. (2018) Patch-Seq Protocol to Analyze the Electrophysiology, Morphology and Transcriptome of Whole Single Neurons Derived From Human Pluripotent Stem Cells. Front Mol Neurosci 11:261
Song, Yan; Botvinnik, Olga B; Lovci, Michael T et al. (2017) Single-Cell Alternative Splicing Analysis with Expedition Reveals Splicing Dynamics during Neuron Differentiation. Mol Cell 67:148-161.e5
Han, Peidong; Bloomekatz, Joshua; Ren, Jie et al. (2016) Coordinating cardiomyocyte interactions to direct ventricular chamber morphogenesis. Nature 534:700-4