{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,29]],"date-time":"2026-10-29T17:14:06Z","timestamp":1793294046889,"version":"4.5.0"},"reference-count":39,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"5","license":[{"start":{"date-parts":[[2021,8,21]],"date-time":"2021-08-21T00:00:00Z","timestamp":1629504000000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["Hepatology"],"published-print":{"date-parts":[[2021,11]]},"abstract":"<jats:sec>\n            <jats:title>Background and Aims<\/jats:title>\n            <jats:p>HSCs and portal fibroblasts (PFs) are the major sources of collagen\u2010producing myofibroblasts during liver fibrosis, depending on different etiologies. However, the mechanisms by which their dynamic gene expression directs the transition from the quiescent to the activated state\u2014as well as their contributions to fibrotic myofibroblasts\u2014remain unclear. Here, we analyze the activation of HSCs and PFs in CCL<jats:sub>4<\/jats:sub>\u2010induced and bile duct ligation\u2013induced fibrosis mouse models, using single\u2010cell RNA sequencing and lineage tracing.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Approach and Results<\/jats:title>\n            <jats:p>We demonstrate that HSCs, rather than PFs, undergo dramatic transcriptomic changes, with the sequential activation of inflammatory, migrative, and extracellular matrix\u2013producing programs. The data also reveal that HSCs are the exclusive source of myofibroblasts in CCL<jats:sub>4<\/jats:sub>\u2010treated liver, while PFs are the major source of myofibroblasts in early cholestatic liver fibrosis. Single\u2010cell and lineage\u2010tracing analysis also uncovers differential gene\u2010expression features between HSCs and PFs; for example, nitric oxide receptor soluble guanylate cyclase is exclusively expressed in HSCs, but not in PFs. The soluble guanylate cyclase stimulator Riociguat potently reduced liver fibrosis in CCL<jats:sub>4<\/jats:sub>\u2010treated livers but showed no therapeutic efficacy in bile duct ligation livers.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p>This study provides a transcriptional roadmap for the activation of HSCs during liver fibrosis and yields comprehensive evidence that the differential transcriptomic features of HSCs and PFs, along with their relative contributions to liver fibrosis of different etiologies, should be considered in developing effective antifibrotic therapeutic strategies.<\/jats:p>\n          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USTC,University of Science and Technology of China,Hefei,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nan","family":"Liu","sequence":"additional","affiliation":[{"name":"Interdisciplinary Research Center on Biology and Chemistry,Shanghai Institute of Organic Chemistry,Chinese Academy of Sciences,Shanghai,China"},{"name":"University of Chinese Academy of Sciences,Beijing,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lingjie","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Histoembryology, Genetics and Developmental Biology,Shanghai Key Laboratory of Reproductive Medicine,Shanghai JiaoTong University School of Medicine,Shanghai,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wu","family":"Wei","sequence":"additional","affiliation":[{"name":"University of Chinese Academy of Sciences,Beijing,China"},{"name":"CAS Key Laboratory of Computational Biology,Shanghai Institute of Nutrition and Health,Chinese Academy of Sciences,Shanghai,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junhao","family":"Hu","sequence":"additional","affiliation":[{"name":"Interdisciplinary Research Center on Biology and Chemistry,Shanghai Institute of Organic Chemistry,Chinese Academy of Sciences,Shanghai,China"},{"name":"University of Chinese Academy of Sciences,Beijing,China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","published-online":{"date-parts":[[2021,8,21]]},"reference":[{"issue":"Suppl 1","key":"hep31987-bib-0001-20250824","first-page":"2","article-title":"Liver diseases: a major, neglected global public health problem requiring urgent actions and large\u2010scale screening","volume":"38","year":"2018","journal-title":"Liver Int"},{"key":"hep31987-bib-0002-20250824","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1016\/j.jhep.2018.09.014","article-title":"Burden of liver diseases in the 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