Single-cell transcriptomics reveals zone-specific alterations of liver sinusoidal endothelial cells in cirrhosis
| Autor: | Yilin Yang, Yasuko Iwakiri, Tingting Su, Sanchuan Lai, Yirang Jung, Matthew McConnell, Teruo Utsumi, Jain Jeong |
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| Rok vydání: | 2020 |
| Předmět: |
Liver Cirrhosis
Endothelial Dysfunction 0301 basic medicine Pathology Cirrhosis Liver fibrosis LSEC liver sinusoidal endothelial cell CD34 Transcriptome Pathogenesis Mice 0302 clinical medicine GSEA gene set enrichment analysis FACS fluorescence-activated cell sorting Endothelial dysfunction Receptor Carbon Tetrachloride Original Research GFP green fluorescent protein scRNA-seq single-cell RNA sequencing 0303 health sciences Chemistry Gastroenterology eNOS endothelial nitric oxide synthase Portal Hypertension HSC hepatic stellate cell 3. Good health Lymphatic system KLF2 qPCR quantitative polymerase chain reaction Liver Fibrosis LyEC lymphatic endothelial cell 030211 gastroenterology & hepatology Single-Cell Analysis medicine.medical_specialty Single cell transcriptomics PBS phosphate-buffered saline BDL bile duct ligation Biology Endocytosis α-SMA α-smooth muscle actin cDNA complementary DNA 03 medical and health sciences Lymphatic Endothelial Cells Downregulation and upregulation scRNA-seq medicine Animals EndMT endothelial-to-mesenchymal transition lcsh:RC799-869 030304 developmental biology NO nitric oxide Hepatology EC endothelial cell Endothelial Cells RNA medicine.disease Capillaries 030104 developmental biology Gene Expression Regulation lcsh:Diseases of the digestive system. Gastroenterology NPC nonparenchymal cell |
| Zdroj: | Cellular and Molecular Gastroenterology and Hepatology, Vol 11, Iss 4, Pp 1139-1161 (2021) Cellular and Molecular Gastroenterology and Hepatology |
| Popis: | Background Dysfunction of liver sinusoidal endothelial cells (LSECs) is permissive for the progression of liver fibrosis and cirrhosis and responsible for its clinical complications. Here, we have mapped the spatial distribution of heterogeneous liver ECs in normal vs cirrhotic mouse livers and identified zone-specific transcriptomic changes of LSECs associated with liver cirrhosis using scRNA-seq technology. Approach & Results Cirrhosis was generated in endothelial specific green fluorescent protein (GFP) reporter mice through carbon tetrachloride inhalation for 12 weeks. GFP-positive liver EC populations were isolated from control and cirrhotic mice by FACS. We identified 6 clusters of liver EC populations including 3 clusters of LSECs, 2 clusters of vascular ECs and 1 cluster of lymphatic ECs. Based on previously reported LSEC-landmarks, we mapped the 3 clusters of LSECs in zones 1, 2, and 3, and determined phenotypic changes in each zone between control and cirrhotic mice. We found genes representing capillarization of LSECs (eg, CD34) as well as extracellular matrix genes were most upregulated in LSECs of zone 3 in cirrhotic mice, which may contribute to the development of basement membranes. LSECs in cirrhotic mice also demonstrated decreased expression of endocytic receptors, most remarkably in zone 3. Transcription factors (Klf2 [Kruppel-like factor-2], Klf4 [Kruppel-like factor-4], and AP-1) that induce nitric oxide production in response to shear stress were downregulated in LSECs of all zones in cirrhotic mice, implying increased intrahepatic vascular resistance. Conclusion This study deepens our knowledge of the pathogenesis of liver cirrhosis at a spatial, cell-specific level, which is indispensable for the development of novel therapeutic strategies to target the most dysfunctional liver ECs. Graphical abstract |
| Databáze: | OpenAIRE |
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