Capillarized Liver Sinusoidal Endothelial Cells Undergo Partial Endothelial-Mesenchymal Transition to Actively Deposit Sinusoidal ECM in Liver Fibrosis
Tissue-specific endothelial cells are more than simply a barrier lining capillaries and are proved to be capable of remarkable plasticity to become active collagen matrix-producing myofibroblasts (MFs) in solid organs with fibrosis. Liver sinusoidal endothelial cells (LSECs) also participate in the...
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Frontiers Media S.A.
2021-07-01
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| Series: | Frontiers in Cell and Developmental Biology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fcell.2021.671081/full |
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| author | Bai Ruan Bai Ruan Bai Ruan Juan-Li Duan Hao Xu Kai-Shan Tao Hua Han Hua Han Guo-Rui Dou Lin Wang |
| author_facet | Bai Ruan Bai Ruan Bai Ruan Juan-Li Duan Hao Xu Kai-Shan Tao Hua Han Hua Han Guo-Rui Dou Lin Wang |
| author_sort | Bai Ruan |
| collection | DOAJ |
| description | Tissue-specific endothelial cells are more than simply a barrier lining capillaries and are proved to be capable of remarkable plasticity to become active collagen matrix-producing myofibroblasts (MFs) in solid organs with fibrosis. Liver sinusoidal endothelial cells (LSECs) also participate in the development of hepatic fibrosis, but the exact roles and underlying mechanism have been poorly understood in addition to capillarization. In this study, we demonstrate, by using single-cell RNA sequencing, lineage tracing, and colocalization analysis, that fibrotic LSECs undergo partial endothelial mesenchymal transition (EndMT) with a subset of LSECs acquiring an MF-like phenotype. These phenotypic changes make LSECs substantial producers of extracellular matrix (ECM) preferentially deposited in liver sinusoids but not septal/portal scars as demonstrated by immunofluorescence in animal models and patients with fibrosis/cirrhosis, likely due to their limited migration. Bioinformatic analysis verifies that LSECs undergo successive phenotypic transitions from capillarization to mesenchymal-like cells in liver fibrosis. Furthermore, blockade of LSEC capillarization by using YC-1, a selective eNOS-sGC activator, effectively attenuates liver damage and fibrogenesis as well as mesenchymal features of LSECs, suggesting that capillarization of LSECs might be upstream to their mesenchymal transition during fibrosis. In conclusion, we report that capillarized LSECs undergo a partial EndMT characterized by increased ECM production without activating cell mobility, leading to perisinusoidal ECM deposition that aggravate liver function and fibrogenesis. Targeting this transitional process may be of great value for antifibrotic treatment of liver fibrosis. |
| first_indexed | 2024-12-19T16:21:54Z |
| format | Article |
| id | doaj.art-168b357a9b45476b939d838ca462ff0d |
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| issn | 2296-634X |
| language | English |
| last_indexed | 2024-12-19T16:21:54Z |
| publishDate | 2021-07-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Cell and Developmental Biology |
| spelling | doaj.art-168b357a9b45476b939d838ca462ff0d2022-12-21T20:14:27ZengFrontiers Media S.A.Frontiers in Cell and Developmental Biology2296-634X2021-07-01910.3389/fcell.2021.671081671081Capillarized Liver Sinusoidal Endothelial Cells Undergo Partial Endothelial-Mesenchymal Transition to Actively Deposit Sinusoidal ECM in Liver FibrosisBai Ruan0Bai Ruan1Bai Ruan2Juan-Li Duan3Hao Xu4Kai-Shan Tao5Hua Han6Hua Han7Guo-Rui Dou8Lin Wang9Department of Hepatobiliary Surgery, Xi-Jing Hospital, Fourth Military Medical University, Xi’an, ChinaState Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi’an, ChinaDepartment of Aviation Medicine, Center of Clinical Aerospace Medicine, Fourth Military Medical University, Xi’an, ChinaDepartment of Hepatobiliary Surgery, Xi-Jing Hospital, Fourth Military Medical University, Xi’an, ChinaDepartment of Hepatobiliary Surgery, Xi-Jing Hospital, Fourth Military Medical University, Xi’an, ChinaDepartment of Hepatobiliary Surgery, Xi-Jing Hospital, Fourth Military Medical University, Xi’an, ChinaDepartment of Hepatobiliary Surgery, Xi-Jing Hospital, Fourth Military Medical University, Xi’an, ChinaState Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi’an, ChinaDepartment of Ophthalmology, Xi-Jing Hospital, Fourth Military Medical University, Xi’an, ChinaDepartment of Hepatobiliary Surgery, Xi-Jing Hospital, Fourth Military Medical University, Xi’an, ChinaTissue-specific endothelial cells are more than simply a barrier lining capillaries and are proved to be capable of remarkable plasticity to become active collagen matrix-producing myofibroblasts (MFs) in solid organs with fibrosis. Liver sinusoidal endothelial cells (LSECs) also participate in the development of hepatic fibrosis, but the exact roles and underlying mechanism have been poorly understood in addition to capillarization. In this study, we demonstrate, by using single-cell RNA sequencing, lineage tracing, and colocalization analysis, that fibrotic LSECs undergo partial endothelial mesenchymal transition (EndMT) with a subset of LSECs acquiring an MF-like phenotype. These phenotypic changes make LSECs substantial producers of extracellular matrix (ECM) preferentially deposited in liver sinusoids but not septal/portal scars as demonstrated by immunofluorescence in animal models and patients with fibrosis/cirrhosis, likely due to their limited migration. Bioinformatic analysis verifies that LSECs undergo successive phenotypic transitions from capillarization to mesenchymal-like cells in liver fibrosis. Furthermore, blockade of LSEC capillarization by using YC-1, a selective eNOS-sGC activator, effectively attenuates liver damage and fibrogenesis as well as mesenchymal features of LSECs, suggesting that capillarization of LSECs might be upstream to their mesenchymal transition during fibrosis. In conclusion, we report that capillarized LSECs undergo a partial EndMT characterized by increased ECM production without activating cell mobility, leading to perisinusoidal ECM deposition that aggravate liver function and fibrogenesis. Targeting this transitional process may be of great value for antifibrotic treatment of liver fibrosis.https://www.frontiersin.org/articles/10.3389/fcell.2021.671081/fullliver fibrosisextracellular matrixmyofibroblastsendothelial cellscapillarizationendothelial-mesenchymal transition |
| spellingShingle | Bai Ruan Bai Ruan Bai Ruan Juan-Li Duan Hao Xu Kai-Shan Tao Hua Han Hua Han Guo-Rui Dou Lin Wang Capillarized Liver Sinusoidal Endothelial Cells Undergo Partial Endothelial-Mesenchymal Transition to Actively Deposit Sinusoidal ECM in Liver Fibrosis Frontiers in Cell and Developmental Biology liver fibrosis extracellular matrix myofibroblasts endothelial cells capillarization endothelial-mesenchymal transition |
| title | Capillarized Liver Sinusoidal Endothelial Cells Undergo Partial Endothelial-Mesenchymal Transition to Actively Deposit Sinusoidal ECM in Liver Fibrosis |
| title_full | Capillarized Liver Sinusoidal Endothelial Cells Undergo Partial Endothelial-Mesenchymal Transition to Actively Deposit Sinusoidal ECM in Liver Fibrosis |
| title_fullStr | Capillarized Liver Sinusoidal Endothelial Cells Undergo Partial Endothelial-Mesenchymal Transition to Actively Deposit Sinusoidal ECM in Liver Fibrosis |
| title_full_unstemmed | Capillarized Liver Sinusoidal Endothelial Cells Undergo Partial Endothelial-Mesenchymal Transition to Actively Deposit Sinusoidal ECM in Liver Fibrosis |
| title_short | Capillarized Liver Sinusoidal Endothelial Cells Undergo Partial Endothelial-Mesenchymal Transition to Actively Deposit Sinusoidal ECM in Liver Fibrosis |
| title_sort | capillarized liver sinusoidal endothelial cells undergo partial endothelial mesenchymal transition to actively deposit sinusoidal ecm in liver fibrosis |
| topic | liver fibrosis extracellular matrix myofibroblasts endothelial cells capillarization endothelial-mesenchymal transition |
| url | https://www.frontiersin.org/articles/10.3389/fcell.2021.671081/full |
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