Perivenous Stellate Cells Are the Main Source of Myofibroblasts and Cancer‐Associated Fibroblasts Formed After Chronic Liver Injuries

Abstract

BaCKgRoUND aND aIMS: Studies of the identity and pathophysiology of fibrogenic HSCs have been hampered by a lack of genetic tools that permit specific and inducible fate-mapping of these cells in vivo. Here, by single-cell RNA sequencing of nonparenchymal cells from mouse liver, we identified transcription factor 21 (Tcf21) as a unique marker that restricted its expression to quiescent HSCs. appRoaCH aND ReSUltS: Tracing Tcf21 + cells by Tcf21-CreER (Cre-Estrogen Receptor fusion protein under the control of Tcf21 gene promoter) targeted ~10% of all HSCs, most of which were located at periportal and pericentral zones. These HSCs were quiescent under steady state but became activated on injuries, generating 62%-67% of all myofibroblasts in fibrotic livers and ~85% of all cancer-associated fibroblasts (CAFs) in liver tumors. Conditional deletion of Transforming Growth Factor Beta Receptor 2 (Tgfbr2) by Tcf21-CreER blocked HSC activation, compromised liver fibrosis, and inhibited liver tumor progression. CoNClUSIoNS:In conclusion, Tcf21-CreER-targeted perivenous stellate cells are the main source of myofibroblasts and CAFs in chronically injured livers. TGFβ signaling links HSC activation to liver fibrosis and tumorigenesis.

Review: Challenges of In Vitro CAF Modelling in Liver Cancers

“…The liver TME is composed of liver resident cells such as liver sinusoidal endothelial cells, HSCs, and Kupffer cells [35] and of other cell types such as myeloid-derived suppressor cells, regulatory T-cells, tumour-associated macrophages, and cancer-associated fibroblasts (CAFs) [39,40]. Recent studies have shown that HSCs are the major source of CAFs in liver cancer, although a small portion of the CAFs can be derived from other cell types, as shown in Figure 1 [9,41]. In conclusion, CAFs appear to be involved in every step of liver cancer development.…”

“…However, the definition by Sahai et al does not allow distinguishing CAFs from common myofibroblasts including non-tumour-associated activated HSCs. In the liver, activated HSCs (aHSCs) are the main myofibroblast source upon injury and fibrogenesis [ 41 , 67 ]. These aHSCs express PDGF-bb, TGF-β, IL-6 and IL-1b.…”

“…In the past few years, new techniques such as sc-RNA seq have shown that heterogeneity also exists in CAFs. Pathway analysis suggests that different subtypes exert different, maybe even opposing functions [ 9 , 41 , 72 ]. These recent findings bring new challenges and opportunities to develop CAF or CAF subtype-targeting strategies to complement currently available anti-cancer therapies.…”

Aspartate reduces liver inflammation and fibrosis by suppressing the NLRP3 inflammasome pathway via upregulating NS3TP1 expression

“…At the cellular level, hepatic stellate cells (HSCs) are arguably the major source of ECM and play a central role in liver fibrogenesis (7)(8)(9). Mechanistically, several key pathways drive HSC activation, except for transforming growth factor-beta (TGF-β) signaling and phosphatidylinositol 3-kinase/ protein kinase B (PI3K/AKT) signaling (1,3).…”

“…Meng’s results (13) suggested that NLRP3 inflammasome activation in HSCs might serve as an early mechanism to turn on the inflammatory response and thereby induce liver fibrosis during Schistosoma infection. Cai et al (14) demonstrated that Angiotensin -(1-7) (Ang-(1-7)) improved liver fibrosis by regulating NLRP3 inflammasome activation induced by Ang II-mediated reactive oxygen species (ROS) production via redox balance modulation.…”