BaCKgRoUND aND aIMS: HSCs and portal fibroblasts (PFs) are the major sources of collagen-producing 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-as well as their contributions to fibrotic myofibroblasts-remain unclear. Here, we analyze the activation of HSCs and PFs in CCL 4 -induced and bile duct ligation-induced fibrosis mouse models, using single-cell RNA sequencing and lineage tracing.
appRoaCH aND ReSUltS:We demonstrate that HSCs, rather than PFs, undergo dramatic transcriptomic changes, with the sequential activation of inflammatory, migrative, and extracellular matrix-producing programs. The data also reveal that HSCs are the exclusive source of myofibroblasts in CCL 4 -treated liver, while PFs are the major source of myofibroblasts in early cholestatic liver fibrosis. Single-cell and lineage-tracing analysis also uncovers differential geneexpression 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 4 -treated livers but showed no therapeutic efficacy in bile duct ligation livers.
CoNClUSIoNS: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. (Hepatology 2021;74:2774-2790.
The
three-dimensional inorganic analogues of 9,10-diboraanthracene,
B2X2(C2B10H10)2 (X = Cl, 1; X = Br, 2), were
attained by salt elimination of Li2C2B10H10 and trihaloboranes. The methyl- and phenyl-substituted
compounds B2Me2(C2B10H10)2 (3) and B2Ph2(C2B10H10)2 (4) were obtained by treating 1 or 2 with
the corresponding Grignard reagents. These compounds were fully characterized
by NMR, cyclic voltammetry (CV), IR, and single-crystal X-ray diffraction
analyses. Experimental (CV and Gutmann–Beckett method) and
computational (fluoride ion affinity, hydride ion affinity and LUMO
energy) results suggest that the order of Lewis acidity is 2 > 1 > 4 > 3 >
SbF5. Treatment of 1 or 2 with
HSiEt3 gave a rare neutral borane–silane adduct,
(Et3SiH)2B2H2(C2B10H10)2 (5). The equilibrium
of 5 in solution was thoroughly investigated by spectroscopy
and quantum calculations.
Mixed-lineage kinase domain-like protein (MLKL) is known as the terminal executor of necroptosis. However, its function outside of necroptosis is still not clear. Herein, we demonstrate that MLKL promotes vascular inflammation by regulating the expression of adhesion molecules ICAM1, VCAM1, and E-selectin in endothelial cells (EC). MLKL deficiency suppresses the expression of these adhesion molecules, thereby reducing EC-leukocyte interaction in vitro and in vivo. Mechanistically, we show that MLKL interacts with RBM6 to promote the mRNA stability of adhesion molecules. In conclusion, this study identified a novel role of MLKL in regulating endothelial adhesion molecule expression and local EC-leukocyte interaction during acute inflammation.
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