Merens Vincent, Knetemann Elisabeth, Gürbüz Elif, De Smet Vincent, Messaoudi Nouredin, Reynaert Hendrik, Verhulst Stefaan, van Grunsven Leo A
Vrije Universiteit Brussel, Liver Cell Biology research group, Laarbeeklaan 103, 1090 Brussel, Belgium.
Department of Gastro-Enterology and Hepatology, Universitair Ziekenhuis Brussel, Brussels, Belgium.
JHEP Rep. 2024 Sep 20;7(1):101223. doi: 10.1016/j.jhepr.2024.101223. eCollection 2025 Jan.
BACKGROUND & AIMS: The progression of chronic liver disease (CLD) is characterized by excessive extracellular matrix deposition, disrupting hepatic architecture and function. Upon liver injury, hepatic stellate cells (HSCs) differentiate towards myofibroblasts and become inflammatory, proliferative and fibrogenic. To date, it is still unclear whether HSC activation is driven by similar mechanisms in different aetiologies.
HSCs from multiple publicly available single-cell RNA-sequencing datasets were annotated and merged into a single-cell HSC activation atlas. Spheroid co-cultures of primary mouse hepatocytes/HSCs (n = 5) and ELISAs on patient plasma samples (n = 80) were performed to validate the mechanistic insight obtained from the HSC atlas.
We established an HSC activation atlas in which HSCs are clearly divided into three distinct transcriptomic profiles: quiescent HSCs, initiatory HSCs and myofibroblasts. These transcriptomic profiles are present in each of the investigated mouse liver injury models as well as in human CLDs, indicating that HSC activation is a conserved process. This activation process is driven by a core set of transcription factors independent of liver injury or species. Furthermore, we reveal novel ligands associated with activation of HSCs in multiple liver injury models and validate the profibrotic effect of parathyroid hormone. Finally, we identify as a conserved marker for quiescent HSCs and a biomarker of liver fibrosis in patients with different CLDs (0.0001).
We reveal unexpected similarities in the regulatory mechanisms of HSCs across diverse liver injury settings and species. The HSC activation atlas has the potential to provide novel insights into liver fibrosis and steer novel treatment options.
This study establishes a single-cell atlas of hepatic stellate cells across various liver injuries, highlighting a conserved activation process between different injuries and across species. The discovery of novel activating ligands and the biomarker COLEC10 in human plasma could be used to enhance diagnostic and therapeutic strategies. Additionally, the conserved activation process supports the use of any mouse model for mechanistic studies and testing of new anti-fibrotic compounds, streamlining preclinical research efforts.
慢性肝病（CLD）的进展以细胞外基质过度沉积为特征，破坏肝脏结构和功能。肝脏损伤时，肝星状细胞（HSCs）向肌成纤维细胞分化，并变得具有炎症性、增殖性和纤维化。迄今为止，尚不清楚在不同病因中，肝星状细胞激活是否由相似机制驱动。
对多个公开的单细胞RNA测序数据集的肝星状细胞进行注释，并合并成一个单细胞肝星状细胞激活图谱。进行原代小鼠肝细胞/肝星状细胞的球体共培养（n = 5）以及对患者血浆样本进行酶联免疫吸附测定（ELISA，n = 80），以验证从肝星状细胞图谱获得的机制性见解。
我们建立了一个肝星状细胞激活图谱，其中肝星状细胞被明确分为三种不同的转录组学特征：静止肝星状细胞、起始肝星状细胞和成肌纤维细胞。这些转录组学特征存在于每个研究的小鼠肝损伤模型以及人类慢性肝病中，表明肝星状细胞激活是一个保守过程。这个激活过程由一组核心转录因子驱动，与肝损伤或物种无关。此外，我们揭示了在多个肝损伤模型中与肝星状细胞激活相关的新配体，并验证了甲状旁腺激素的促纤维化作用。最后，我们确定COLEC10是静止肝星状细胞的保守标志物以及不同慢性肝病患者肝纤维化的生物标志物（P<0.0001）。
我们揭示了在不同肝损伤情况和物种中肝星状细胞调节机制的意外相似性。肝星状细胞激活图谱有可能为肝纤维化提供新见解并指导新的治疗选择。
本研究建立了跨各种肝损伤的肝星状细胞单细胞图谱，突出了不同损伤之间以及跨物种的保守激活过程。在人血浆中发现新的激活配体和生物标志物COLEC10可用于加强诊断和治疗策略。此外，保守的激活过程支持使用任何小鼠模型进行机制研究和新抗纤维化化合物的测试，简化临床前研究工作。
