Humanized Mouse Liver Reveals Endothelial Control of Essential Hepatic Metabolic Functions

Overview

Journal Cell

Publisher Cell Press

Specialty Cell Biology

Date 2023 Aug 10

PMID 37562401

Authors

Eleanna Kaffe

Manolis Roulis

Jun Zhao

Rihao Qu

Esen Sefik

Haris Mirza

Jing Zhou

Yunjiang Zheng

Georgia Charkoftaki

Vasilis Vasiliou

Daniel F Vatner

Wajahat Z Mehal

Yuval Kluger

Richard A Flavell

Affiliations

Soon will be listed here.

Abstract

Hepatocytes, the major metabolic hub of the body, execute functions that are human-specific, altered in human disease, and currently thought to be regulated through endocrine and cell-autonomous mechanisms. Here, we show that key metabolic functions of human hepatocytes are controlled by non-parenchymal cells (NPCs) in their microenvironment. We developed mice bearing human hepatic tissue composed of human hepatocytes and NPCs, including human immune, endothelial, and stellate cells. Humanized livers reproduce human liver architecture, perform vital human-specific metabolic/homeostatic processes, and model human pathologies, including fibrosis and non-alcoholic fatty liver disease (NAFLD). Leveraging species mismatch and lipidomics, we demonstrate that human NPCs control metabolic functions of human hepatocytes in a paracrine manner. Mechanistically, we uncover a species-specific interaction whereby WNT2 secreted by sinusoidal endothelial cells controls cholesterol uptake and bile acid conjugation in hepatocytes through receptor FZD5. These results reveal the essential microenvironmental regulation of hepatic metabolism and its human-specific aspects.

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