Title: Expression of Liver Sinusoidal Endothelial Cell Markers can be induced in Endothelial Stem Cells by Overexpression of C-MAF, GATA4 and MEIS2
Authors: de Haan, Willeke
Dheedene, Wouter
Boon, Ruben
Hoekman, Boukje
Vandervoort, Petra
Verfaillie, Catherine
Luttun, Aernout
Issue Date: 3-Dec-2015
Conference: Biology meets technology for liver toxicity testing location:Leuven date:2-3 December 2015
Abstract: Liver Sinusoidal Endothelial Cells (LSECs) are lining the capillaries of the liver and are the initial cells that come into contact with toxins and drugs in the bloodstream. Damage of LSECs is an early step in liver toxicity. LSECs are highly specialized cells mediating uptake of agents from the blood to the hepatocytes, hereto, they form fenestrae and express scavenger receptors that allow selective transport towards hepatocytes. Therefore LSECs are a crucial component of an in vitro liver model to predict toxicity. LSECs are however difficult to obtain and rapidly loose their specific properties when cultured. We aimed to generate LSECs from endothelial stem cells including HUVECs and BOECs that can be used in an in vitro liver toxicity model.
We identified ~30 genes that are highly enriched in LSECs among which 7 transcription factors. We generated lentiviruses to induce the expression of the 7 TFs in human umbilical vein ECs (HUVECs) and blood outgrowth ECs (BOECs). C-MAF, GATA4 and MEIS2 induced expression of several LSEC markers HUVECs and BOECS whereas ZEB2, TCFEC, CUX2 and HOXB5 had only minor roles. HUVECs with lentivirus induced overexpression of a combination of c-MAF, GATA4 and MEIS2 showed an upregulation of about 50% of the LSEC signature genes including that of L-SIGN, MRC1 and LGMN. As previously described in literature, a combination of TGF-β inhibition and adrenomedullin induced the expression of LSEC markers including that of F8, STAB2 and LYVE1. To further stimulate LSEC features in HUVECs and BOECS we are now studying the role of TF overexpression in combination with TGFβ inhibition and adrenomedullin or with hypoxia to generate a more physiological environment.
We conclude that c-MAF, MEIS2 and GATA4 are major regulators of the LSEC phenotype. Overexpression of c-MAF, MEIS2 and GATA4 may form the basis of a strategy to differentiate endothelial stem cells into LSECs.
Publication status: published
KU Leuven publication type: IMa
Appears in Collections:Molecular and Vascular Biology
Stem Cell Biology and Embryology (+)

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