Beijing Clinical Research Institute, Beijing, China.
Experimental and Translational Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China.
Hepatology. 2023 Oct 1;78(4):1118-1132. doi: 10.1097/HEP.0000000000000423. Epub 2023 Apr 27.
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.
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.
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.
细胞外基质的过度沉积和交联增加了肝脏密度和硬度，促进了纤维化，并增加了对纤维蛋白溶解的抵抗。肝纤维化的一个新的治疗机会是靶向细胞外基质的组成或阻断与周围细胞的致病通讯。然而，触发肝纤维化的细胞外变化的类型和程度取决于潜在的病因。我们的目的是揭示不依赖病因的基质组基因，这些基因与肝纤维化具有临床相关性。
我们使用来自不同病因的肝纤维化病例的转录组谱，来识别和验证肝纤维化特异性基质组基因（LFMGs）及其临床和生物学相关性。通过批量和单细胞 RNA 测序，进一步探索了 LFMGs 在肝纤维化进展和消退的小鼠模型中的失调模式和细胞景观。我们确定了 35 个不依赖病因的 LFMGs，代表定义肝纤维化的 LFMG 特征。LFMG 特征的表达依赖于组织学严重程度，并在退化的肝脏中减少。即使有相同的病理评分，肝纤维化患者也可以分为 LFMG 低和 LFMG 高，具有可区分的临床、细胞和分子特征。单细胞 RNA 测序显示，微纤维相关蛋白 4+激活的 HSC 在 LFMG 高患者中增加，并且主要负责 LFMG 特征的表达和失调。
微纤维相关蛋白 4+激活的 HSC 衍生的 LFMG 特征对具有不同临床和生物学特征的肝纤维化患者进行分类。我们的发现揭示了使用传统组织学评估无法检测到的肝活检中的隐藏信息。
