Androgen Regulates SARS-CoV-2 Receptor Levels and Is Associated with Severe COVID-19 Symptoms in Men [bulk RNA-Seq]

Here, we established a high-throughput drug screening strategy to identify therapeutic candidates that reduce ACE2 levels in human embryonic stem cell (hESC) derived cardiac cells and lung organoids. Drug target analysis of validated hit compounds, including 5 alpha reductase inhibitors, revealed androgen signaling as a key modulator of ACE2 levels. Treatment with antiandrogenic drugs reduced ACE2 expression in both human cardiac and lung epithelial cells and protected hESC-derived lung organoids against SARS-CoV-2 infection. To build an in vitro model of viral infection in human lung tissue, we set out to generate lung organoids from hESC using a slightly modified combination of previously established differentiation methods (Carvalho et al., 2019; Jacob et al., 2017; Miller et al., 2019). We performed single cell RNA sequencing of fully differentiated organoids to unbiasedly characterize the cell types present and validate them as a model of SARS-CoV-2 infection and antiandrogenic drug treatment. Cells during HLO differentiation were harvested on Day 0 (hPSCs), 5, 9, 15, 25, 35, and 50, in duplicates, and used for RNAseq library preparation.