4.6 Article

Heterogeneity of Hepatic Stellate Cells in Fibrogenesis of the Liver: Insights from Single-Cell Transcriptomic Analysis in Liver Injury

Journal

CELLS
Volume 10, Issue 8, Pages -

Publisher

MDPI
DOI: 10.3390/cells10082129

Keywords

single-cell RNA sequencing; hepatic stellate cell sublineage; myofibroblast; liver fibrosis; carbon tetrachloride

Categories

Funding

  1. Showalter Young Investigator Award (CTSI, Indiana University)
  2. National Institute of Health [P01HL134599, R01HL145060, U01AI138897, R01 HL135657]
  3. George M. O'Brien Center for Advanced Renal Microscopic Analysis Fellowship

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This study identified multiple subpopulations of HSCs and characterized their unique roles and characteristics during liver injury, including differentiating into myofibroblasts and potential involvement in liver regeneration, immune reaction, and vascular remodeling. The scRNA-seq data provided insight into the dynamic transition from HSCs to myofibroblasts in response to liver injury, highlighting the heterogeneity and functional diversity of HSCs. The findings also suggest similarities between the heterogeneity of HSCs in injured mouse livers and cirrhotic human livers.
Background & Aims: Liver fibrosis is a pathological healing process resulting from hepatic stellate cell (HSC) activation and the generation of myofibroblasts from activated HSCs. The precise underlying mechanisms of liver fibrogenesis are still largely vague due to lack of understanding the functional heterogeneity of activated HSCs during liver injury. Approach and Results: In this study, to define the mechanism of HSC activation, we performed the transcriptomic analysis at single-cell resolution (scRNA-seq) on HSCs in mice treated with carbon tetrachloride (CCl4). By employing LRAT-Cre:Rosa26(mT/mG) mice, we were able to isolate an activated GFP-positive HSC lineage derived cell population by fluorescence-activated cell sorter (FACS). A total of 8 HSC subpopulations were identified based on an unsupervised analysis. Each HSC cluster displayed a unique transcriptomic profile, despite all clusters expressing common mouse HSC marker genes. We demonstrated that one of the HSC subpopulations expressed high levels of mitosis regulatory genes, velocity, and monocle analysis indicated that these HSCs are at transitioning and proliferating phases at the beginning of HSCs activation and will eventually give rise to several other HSC subtypes. We also demonstrated cell clusters representing HSC-derived mature myofibroblast populations that express myofibroblasts hallmark genes with unique contractile properties. Most importantly, we found a novel HSC cluster that is likely to be critical in liver regeneration, immune reaction, and vascular remodeling, in which the unique profiles of genes such as Rgs5, Angptl6, and Meg3 are highly expressed. Lastly, we demonstrated that the heterogeneity of HSCs in the injured mouse livers is closely similar to that of cirrhotic human livers. Conclusions: Collectively, our scRNA-seq data provided insight into the landscape of activated HSC populations and the dynamic transitional pathway from HSC to myofibroblasts in response to liver injury.

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