Yashaswini, Chittampalli N, Qin, Tianyue, Bhattacharya, Dipankar, Amor, Corina, Lowe, Scott, Lujambio, Amaia, Wang, Shuang, Friedman, Scott L (March 2024) Phenotypes and ontogeny of senescent hepatic stellate cells in metabolic dysfunction-associated steatotic liver disease. Journal of Hepatology. S0168-8278(24)00197. ISSN 0168-8278
Abstract
BACKGROUND: Hepatic stellate cells (HSCs) are the key drivers of fibrosis in metabolic dysfunction-associated steatotic liver disease (MASLD), the fastest growing cause of hepatocellular carcinoma worldwide. HSCs are heterogenous, and a senescent subset of HSCs is implicated in hepatic fibrosis and HCC. Administration of anti-uPAR (urokinase-type plasminogen activator receptor) CAR T cells depletes senescent HSCs and attenuates fibrosis in murine liver injury models, including MASLD. However, the comprehensive features of senescent HSCs in MASLD, as well as their cellular ontogeny have not been characterized. AIMS AND METHODS: Our aims were to comprehensively characterize and define the origin of senescent HSCs in human and murine MASLD by integrating senescence-associated beta galactosidase activity with immunostaining, flow cytometry and single nuclear RNA-sequencing (snRNAseq). We integrated the immunohistochemical profile with a senescence score applied to snRNAseq data to characterize senescent HSCs, and mapped the evolution of uPAR expression in MASLD. RESULTS: Using pseudotime trajectory analysis, we establish that senescent HSCs arise from activated HSCs. While uPAR is expressed in MASLD, the magnitude and cell-specificity of its expression evolve with disease stage, such that in early disease, uPAR is more specific to activated and senescent HSCs, and in late disease, uPAR is also expressed by myeloid-lineage cells including Trem2+ macrophages and myeloid-derived suppressor cells. Furthermore, we identify novel surface proteins expressed on senescent HSCs in human and murine MASLD that could be exploited as therapeutic targets. CONCLUSIONS: These data define features of HSC senescence in human and murine MASLD, establishing an important blueprint to target these cells as part of future antifibrotic therapy. LAY SUMMARY: Hepatic stellate cells (HSCs) are the primary drivers of scarring in chronic diseases of the liver. As injury develops, a subset of HSCs become senescent; these cells are non-proliferative and pro-inflammatory, thereby contributing to worsening liver injury. Here we show that senescent HSCs are expanded in metabolic dysfunction-associated steatotic liver disease (MASLD) in humans and mice, and we trace their cellular origin from the activated HSC subset. We further characterize expression of uPAR (urokinase plasminogen activated receptor), a protein that marks senescent HSCs, and report that uPAR is also expressed by activated HSCs in early injury, and immune cells as liver injury advances. We have integrated high resolution single nuclei sequencing with immunostaining and flow cytometry to identify five other novel proteins expressed by senescent HSCs, including mannose receptor CD206, which will facilitate future efforts to clear senescent HSCs to treat fibrosis.
| Item Type: | Paper |
|---|---|
| Subjects: | organs, tissues, organelles, cell types and functions > cell types and functions > cell functions organs, tissues, organelles, cell types and functions > cell types and functions organs, tissues, organelles, cell types and functions > organs types and functions > liver organs, tissues, organelles, cell types and functions > organs types and functions organs, tissues, organelles, cell types and functions organs, tissues, organelles, cell types and functions > cell types and functions > cell functions > senescence |
| CSHL Authors: | |
| Communities: | CSHL Cancer Center Program > Cellular Communication in Cancer Program CSHL labs > Lowe lab CSHL Cancer Center Program CSHL labs > Amor lab |
| SWORD Depositor: | CSHL Elements |
| Depositing User: | CSHL Elements |
| Date: | 18 March 2024 |
| Date Deposited: | 31 May 2024 17:58 |
| Last Modified: | 20 Nov 2024 16:25 |
| PMCID: | PMC11269047 |
| Related URLs: | |
| URI: | https://repository.cshl.edu/id/eprint/41573 |
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