Roadmap to efficiently generate human artery and vein endothelial cells from pluripotent stem cells

Kyle Loh, PhD

Stanford University, Assistant Professor and The Anthony DiGenova Endowed Faculty Scholar

Abstract: Endothelial cells—encompassing molecularly-distinct arteries versus veins—pervade all tissues and have manifold roles in health and disease, and also likely contribute to congenital heart defects. What instigates human endothelial cell diversity and how can we recreate such diversity in vitro? Here we efficiently differentiate human pluripotent stem cells through a sequence of branching lineage choices into artery or vein endothelial cells, within 3-4 days. This roadmap encompasses the stepwise changes in extracellular signals, gene expression, chromatin state and cell-surface markers during specialization of artery vs. vein cells from their mesodermal precursors, including a two-step process for vein specification. This thus provides an informative reference map for human artery and vein development. The newfound capability to rapidly and efficiently generate human artery-specific and vein-specific endothelial cells en masse should avail tissue engineering, disease modeling and other diverse applications that hinge on a large-scale supply of human endothelial cells.

SARS-CoV-2 infection of human iPSC-derived cardiac cells predicts novel cytopathic features in hearts of COVID-19 patients

Serah Kang, PhD

UCSF & Gladstone Institutes, Postdoctoral Fellow (McDevitt Lab)

Abstract: Although COVID-19 causes cardiac dysfunction in up to 25% of patients, its pathogenesis remains unclear. Exposure of human iPSC-derived heart cells to SARS-CoV-2 revealed productive infection and robust transcriptomic and morphological signatures of damage, particularly in cardiomyocytes. Transcriptomic disruption of structural proteins corroborated adverse morphologic features, which included a distinct pattern of myofibrillar fragmentation and numerous iPSC-cardiomyocytes lacking nuclear DNA. Human autopsy specimens from COVID-19 patients displayed similar sarcomeric disruption, as well as cardiomyocytes without DNA staining. These striking cytopathic features provide new insights into SARS-CoV-2 induced cardiac damage, offer a platform for discovery of potential therapeutics, and raise serious concerns about the long-term consequences of COVID-19.