Wen Zhang

The liver possesses a remarkable regenerative capacity following injury, a process fundamentally orchestrated by the dynamic extracellular matrix (ECM). Far beyond a passive scaffold, the liver matrisome functions as an integrative mechano-biochemical circuit. It comprises a core structural network together with regulatory non-core components that collectively establish a dynamic niche. This niche stores and releases mitogenic cues, transmits mechanical forces, and coordinates multicellular crosstalk. Through receptors like integrins and mechanosensitive channels, ECM-derived signals converge on key pathways, including Hippo-YAP/TAZ and Wnt/β-catenin, to drive hepatocyte proliferation and tissue restructuring. The balance between matrix stabilization and remodeling dictates the outcome, guiding physiological regeneration versus fibrotic progression. Consequently, the ECM emerges as a central therapeutic target and a blueprint for engineering strategies aimed at restoring liver function. Strategies to recalibrate its composition, mechanics, and remodeling, from pharmacological inhibitors to bioengineered decellularized ECM scaffolds, hold significant potential for steering liver repair and combating chronic liver disease.

The liver possesses a remarkable regenerative capacity following injury, a process fundamentally orchestrated by the dynamic extracellular matrix (ECM). Far beyond a passive scaffold, the liver matrisome functions as an integrative mechano-biochemical circuit. It comprises a core structural network and regulatory non-core components that together establish a dynamic niche. This niche stores and releases mitogenic cues, transmits mechanical forces, and coordinates multicellular crosstalk. Through receptors like integrins and mechanosensitive channels, ECM-derived signals converge on key pathways, including Hippo-YAP/TAZ and Wnt/β-catenin, to drive hepatocyte proliferation and tissue restructuring. The balance between matrix stabilization and remodeling dictates the outcome, guiding physiological regeneration versus fibrotic progression. Consequently, the ECM emerges as a central therapeutic target and a blueprint for engineering strategies aimed at restoring liver function. Strategies to recalibrate its composition, mechanics, and remodeling, from pharmacological inhibitors to bioengineered decellularized ECM scaffolds, hold transformative potential for steering liver repair and combating chronic disease.

Background: Lysyl oxidase (LOX) family members (LOX and LOXL1 to 4) are crucial copper-dependent enzymes responsible for cross-linking collagen and elastin. Previous studies have revealed that LOX and LOXL1 are the most dramatically dysregulated LOX isoforms during liver fibrosis. However, the crosstalk between them and the underlying mechanisms involved in the profibrotic behaviors of HSCs, as well as the progression of liver fibrosis, remain unclear. Methods: pCol9GFP-HS4,5^Tg mice, Loxl1 ^fl/fl Gfap ^Cre mice, human HSC line, and primary HSCs were enrolled to study the dysregulation pattern, profibrotic roles, and the potential mechanisms of LOX and LOXL1 interaction involved in the myofibroblast-like transition of HSCs and liver fibrogenesis. Results: LOX and LOXL1 were synergistically upregulated during liver fibrogenesis, irrespective of etiology, together orchestrating the profibrotic behaviors of HSCs. LOX and LOXL1 coregulated in HSCs, whereas LOXL1 dominated in the coregulation loop. Interestingly, the interaction between LOXL1 and LOX prolonged their half-lives, specifically enhancing the Notch signal-mediated myofibroblast-like transition of HSCs. Selective disruption of Loxl1 in Gfap ⁺ HSCs deactivated the Notch signal, inhibited HSC activation, and relieved carbon tetrachloride-induced liver fibrosis. Conclusions: Our current study confirmed the synergistic roles and the underlying mechanisms of LOXL1 and LOX crosstalk in the profibrotic behaviors of HSCs and liver fibrosis progression, providing experimental evidence for further clear mechanism-based anti-LOXL1 strategy development in the therapy of liver fibrosis.

Background & Aims: Excessive deposition and crosslinking of extracellular matrix increases liver density and stiffness, promotes fibrogenesis, and increases resistance to fibrinolysis. An emerging therapeutic opportunity in liver fibrosis is to target the composition of the extracellular matrix or block pathogenic communication with surrounding cells. However, the type and extent of extracellular changes triggering liver fibrosis depend on the underlying etiology. Our aim was to unveil matrisome genes not dependent on etiology, which are clinically relevant to liver fibrosis. Approach & Results: We used transcriptomic profiles from liver fibrosis cases of different etiologies to identify and validate liver fibrosis-specific matrisome genes (LFMGs) and their clinical and biological relevance. Dysregulation patterns and cellular landscapes of LFMGs were further explored in mouse models of liver fibrosis progression and regression by bulk and single-cell RNA sequencing. We identified 35 LFMGs, independent of etiology, representing an LFMG signature defining liver fibrosis. Expression of the LFMG signature depended on histological severity and was reduced in regressive livers. Patients with liver fibrosis, even with identical pathological scores, could be subclassified into LFMG^Low and LFMG^High, with distinguishable clinical, cellular, and molecular features. Single-cell RNA sequencing revealed that microfibrillar-associated protein 4⁺ activated HSC increased in LFMG^High patients and were primarily responsible for the LFMG signature expression and dysregulation. Conclusions: The microfibrillar-associated protein 4⁺ -activated HSC-derived LFMG signature classifies patients with liver fibrosis with distinct clinical and biological characteristics. Our findings unveil hidden information from liver biopsies undetectable using traditional histologic assessments.