hESCs-derived organoids achieve liver zonation by LSEC modulation

Abstract

Liver zonation, essential for diverse physiological functions, is lacking in existing organoid models, hindering their ability to recapitulate liver development and pathogenesis. Addressing this gap, we explored the feasibility of achieving zonated organoid by co-culturing human embryonic stem cells (hESCs) derived hepatocytes with hESCs derived liver sinusoidal endothelial cells (LSECs) exhibiting characteristics of either the liver lobules pericentral (PC) or periportal (PP) regions. Introducing zonated LSECs with variable WNT2 signaling subtly regulate hepatocyte zonation, resulting in noticeable metabolic function changes. Considering the lipid metabolism variations in PC and PP organoids, we constructed biomimetic zonated non-alcoholic fatty liver disease (NAFLD) organoids and revealed that glucagon-like peptide-1 receptor agonist (GLP-1RA) target LSECs, but not hepatocytes, indicating potential therapeutic mechanisms of GLP-1RA in NAFLD alleviation. This study highlights the crucial role of non-parenchymal cells in organoids for recapitulating niche heterogeneity, offering further insights for drug discovery and in vitro modeling of organ heterogeneity. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=184 SRC="FIGDIR/small/592562v1_figu1.gif" ALT="Figure 1"> View larger version (57K): org.highwire.dtl.DTLVardef@1907c9eorg.highwire.dtl.DTLVardef@e5a76borg.highwire.dtl.DTLVardef@152a1dcorg.highwire.dtl.DTLVardef@981f_HPS_FORMAT_FIGEXP M_FIG Graphical AbstractSchematic of hESCs-derived liver zonation organoids C_FIG