Generation of functional liver sinusoidal endothelial cells from human pluripotent stem-cell-derived venous angioblasts

Blair K. Gage, Jeff C. Liu, Brendan T. Innes, Sonya A. MacParland, Ian D. McGilvray, Gary D. Bader, and Gordon M. Keller.
Cell Stem Cell (2020). DOI:

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Summary

Liver sinusoidal endothelial cells (LSECs) form a highly specialized microvasculature that plays a critical role in liver function and disease. To better understand this role, we developed a strategy to generate LSECs from human pluripotent stem cells (hPSCs) by first optimizing the specification of arterial and venous angioblasts and derivative endothelial populations. Induction of a LSEC-like fate by hypoxia, cyclic AMP (cAMP) agonism, and transforming growth factor β (TGF-β) inhibition revealed that venous endothelial cells responded more rapidly and robustly than the arterial cells to upregulate LSEC markers and functions in vitro. Upon intrahepatic transplantation in neonates, venous angioblasts engrafted the liver and generated mature, fenestrated LSECs with scavenger functions and molecular profiles of primary human LSECs. When transplanted into the liver of adult mice, angioblasts efficiently gave rise to mature LSECs with robust factor VIII (FVIII) production. Humanization of the murine liver with hPSC-derived LSECs provides a tractable system for studying the biology of this key liver cell type.

hPSC-derived LSECs

scClustViz of hPSC-derived LSECs

Explore this data interactively in your web browser
or
Download for viewing in with scClustViz on your computer.

with the Human Liver Atlas

scClustViz of hPSC-derived LSECs

Explore this data interactively in your web browser
or
Download for viewing with scClustViz on your computer.

To explore this data offline in R, download the zip file(s) above, and unzip them to the directory of your choice.
Then install scClustViz using the commands below:

# Installation (takes time, but only run once):
install.packages("devtools","BiocManager")
BiocManager::install("org.Hs.eg.db")
devtools::install_github("BaderLab/scClustViz")

Then to open an interactive scClustViz RShiny session on your computer, run the following commands (replacing path/to/file with the path to the unzipped data file you downloaded above):

# View the data:
library(scClustViz)
runShiny("path/to/file/hPSCderivedLSECs.RData",
         annotationDB="org.Hs.eg.db",
         rownameKeytype="SYMBOL",
         imageFileType="png")