Liver Endothelial Heg Regulates Vascular/Biliary Network Patterning and Metabolic Zonation Via Wnt Signaling

Zhu, Shichao; Rao, Xiyun; Qian, Yude; Chen, Jinbiao; Song, Renhua; Yan, Han; Yang, Xi; Hu, Junhao; Wang, Xiaohong; Han, Zhiming; Zhu, Yi; Liu, Renjing; Wong, Justin Jong-Leong; McCaughan, Geoffrey W.; Zheng, Xiangjian

doi:10.1016/j.jcmgh.2022.02.010

Cited by 11 publications

(13 citation statements)

References 52 publications

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“…Notch has also been shown to regulates c-kit positive ECs to contribute to LZ and LR through Wnt2 (Duan et al, 2022). Finally, deletion of endothelial Heart-of-glass (Heg) changed vascular 3D-patterning and disrupted LZ through impaired Wnt2, Wnt9b , and Rspo3 expression (Zhu et al, 2022). Whether these various perturbations are because each of these regulates Wnt2 and Wnt9b expression and/or secretion from ECs or it is due to effect of these alterations on endothelial cell function and identity leading to secondary changes in Wnts, remains unclear and requires further careful analysis.…”

Section: Discussionmentioning

confidence: 99%

Dynamic control of metabolic zonation and liver repair by endothelial cell Wnt2 and Wnt9b revealed by single cell spatial transcriptomics using Molecular Cartography

Liu

Bian

et al. 2022

Preprint

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The conclusive identity of Wnt proteins regulating liver zonation (LZ) and regeneration (LR) remains unclear despite an undisputed role of b-catenin. Using single-cell analysis of liver cells from various species, a conserved Wnt2 and Wnt9b expression in endothelial cells (ECs) in zone 3 shown to be the major Wnt cell source, was identified. Conditional EC-elimination of Wnt2 and Wnt9b led to perturbation of LZ with not only loss of b-catenin targets in zone 3, but also re-appearance of zone 1 genes in zone 3, unraveling dynamicity as revealed by single-cell spatial transcriptomics using Molecular Cartography. Defective LR observed in the knockouts phenocopied other models of defective hepatic Wnt signaling. Administration of a tetravalent antibody to activate Wnt signaling rescued LZ and LR in the knockouts. Molecular Cartography on the livers of the agonist-treated animal revealed changes in LZ. Administration of the agonist also promoted LR in acetaminophen overdose acute liver failure (ALF) fulfilling an unmet clinical need. Overall, we report an unequivocal role of EC-Wnt2 and Wnt9b in LZ and LR and show the role of Wnt activators as regenerative therapy for ALF.

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Section: Discussionmentioning

confidence: 99%

Dynamic control of metabolic zonation and liver repair by endothelial cell Wnt2 and Wnt9b revealed by single cell spatial transcriptomics using Molecular Cartography

Liu

Bian

et al. 2022

Preprint

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“…In addition to central vein-associated angiocrine Wnt signaling, endothelial tyrosine kinase with Ig-like and EGF-like domains 1/2 (Tie1/2), 10 Notch, 11,12 c-Maf, [13][14][15][16] Heg, 17 and periportal Dll4 and Esm1 16,18 also participate to hepatic and endothelial zonation. 5,6,[19][20][21][22] Briefly, paired endothelial cell/hepatocyte sequencing was originally utilized to develop a panel of pericentral to periportal endothelial functional landmark genes (70 each).…”

Section: Zonation In Healthy Liver By Asigmentioning

confidence: 99%

Angiocrine Signaling in Sinusoidal Health and Disease

2023

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Liver sinusoidal endothelial cells (LSECs) are key players in maintaining hepatic homeostasis. They also play crucial roles during liver injury by communicating with liver cell types as well as immune cells and promoting portal hypertension, fibrosis and inflammation. Cutting-edge technology, such as single cell and spatial transcriptomics, have revealed the existence of distinct LSEC subpopulations with a clear zonation in the liver. The signals released by LSECs are commonly called “angiocrine signaling”. In this review, we summarize the role of angiocrine signaling in health and disease, including zonation in healthy liver, regeneration, fibrosis, portal hypertension, non-alcoholic fatty liver disease, alcohol-associated liver disease, aging, drug-induced liver injury, and ischemia/reperfusion, as well as potential therapeutic advances. In conclusion, sinusoidal endotheliopathy is recognized in liver disease and promising pre-clinical studies are paving the path towards LSEC-specific pharmacotherapies.

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“…LSECs which exert gatekeeper roles in maintaining liver metabolic zonation 20 could be roughly classi ed into three subpopulations, the periportal (zone-1), sinusoidal (zone-2) and pericentral (zone-3) LSECs [21][22][23] . Although the spatial and molecular heterogeneity of LSECs is well recognized, the functional heterogeneity of liver endothelium in manipulating hepatic pathologic challenges including liver Page 4/28 regeneration, brosis, steatosis, and cancer is still understudied 24,25 .…”

Section: Introductionmentioning

confidence: 99%

Age-related liver endothelial zonation triggers steatohepatitis by inactivating pericentral endothelium-derived C-kit

et al. 2022

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Aging reprogramming liver endothelial zonation triggers steatohepatitis by inactivating pericentral endothelium-derived C-kit Juanli Duan fourth military medical university Jingjing Liu fourth military medical university Bai Ruan fourth military medical university Jian Ding fourth military medical university Zhiqiang Fang fourth military medical university Hao Xu fourth military medical university Ping Song fourth military medical university Chen Xu fourth military medical university Zhiwen Li fourth military medical university Wei Du fourth military medical university

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Liver Endothelial Heg Regulates Vascular/Biliary Network Patterning and Metabolic Zonation Via Wnt Signaling

Cited by 11 publications

References 52 publications

Dynamic control of metabolic zonation and liver repair by endothelial cell Wnt2 and Wnt9b revealed by single cell spatial transcriptomics using Molecular Cartography

Dynamic control of metabolic zonation and liver repair by endothelial cell Wnt2 and Wnt9b revealed by single cell spatial transcriptomics using Molecular Cartography

Angiocrine Signaling in Sinusoidal Health and Disease

Age-related liver endothelial zonation triggers steatohepatitis by inactivating pericentral endothelium-derived C-kit

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