The role of microfibril-associated glycoprotein-1 in experimental liver fibrosis [scRNA-seq]

Microfibril-associated glycoprotein-1 (MAGP-1), a critical component of extracellular matrix (ECM) microfibrils, plays a pivotal role in liver fibrosis, although its precise function in this process remains elusive. Our research underscores that MAGP-1 (Mfap2) is predominantly expressed in activated hepatic stellate cells (HSCs) and exhibits heightened levels in advanced liver fibrosis. Deletion of MAGP-1 showcased limited impact on overall collagen deposition following CCl4 stimulation. However, it notably heightened intrahepatic inflammatory infiltration within lobular regions, hastened ECM stabilization through the upregulation of insoluble matrisome constituents within the ECM, and triggered focal adhesion (FA) signaling in HSCs, hindering the regression of liver fibrosis upon cessation of CCl4 treatment. scRNA-seq was performed on liver nonparenchymal cells isolated from CCl4-injected Mfap2+/+ and Mfap2-/- mice (8 weeks).

微纤维相关糖蛋白-1（Microfibril-associated glycoprotein-1, MAGP-1）作为细胞外基质（extracellular matrix, ECM）微纤维的关键组成成分，在肝纤维化进程中发挥关键作用，但其在该过程中的具体功能仍未明确。本研究证实，MAGP-1（又称Mfap2）主要在活化的肝星状细胞（hepatic stellate cells, HSCs）中表达，且在晚期肝纤维化组织中表达水平升高。在四氯化碳（CCl4）诱导刺激后，MAGP-1基因敲除对整体胶原沉积的影响有限。然而，该基因的缺失可显著加剧肝小叶区域的肝内炎症浸润，通过上调细胞外基质中不溶性基质组（matrisome）成分加速细胞外基质的稳定化，并激活肝星状细胞内的黏着斑（focal adhesion, FA）信号通路，从而在停止四氯化碳给药后阻碍肝纤维化的消退。本研究对从注射四氯化碳的8周龄Mfap2+/+与Mfap2-/-小鼠中分离的肝脏非实质细胞进行了单细胞RNA测序（single-cell RNA sequencing, scRNA-seq）。