Scar‐Degrading Endothelial Cells as a Treatment for Advanced Liver Fibrosis

• Published in: Advanced science Vol. 10; no. 4; pp. e2203315 - n/a
• Main Authors: Zhao, Peng, Sun, Tian, Lyu, Cheng, Liang, Kaini, Niu, Yudi, Zhang, Yuying, Cao, Chenhui, Xiang, Canhong, Du, Yanan
• Format: Journal Article
• Language: English
• Published: Germany John Wiley & Sons, Inc 01-02-2023; John Wiley and Sons Inc; Wiley
• Subjects: Animals; Candidates; Cells; Cicatrix; Collagen; Endothelial Cells - metabolism; extracellular matrix degradation; Fibroblasts; high‐throughput screening system; Humans; Liver cirrhosis; Liver Cirrhosis - therapy; liver fibrosis; liver sinusoidal endothelial cells; Matrix Metalloproteinase 9 - metabolism; Mice; Neutrophils; Scanning electron microscopy; liver fibrosis; liver sinusoidal endothelial cells; extracellular matrix degradation; high-throughput screening system
• ISSN: 2198-3844; 2198-3844
• DOI: 10.1002/advs.202203315

Deposition of extracellular matrix (ECM) in the liver is an important feature of liver cirrhosis. Recovery from liver cirrhosis is physiologically challenging, partially due to the ECM in scar tissue showing resistance to cell‐mediated degradation by secreted matrix metalloproteinases (MMPs). Here, a cell‐mediated ECM‐degradation screening system (CEDSS) in vitro is constructed for high‐throughput searching for cells with tremendous degradation ability. ECM‐degrading liver sinusoidal endothelial cells (dLSECs) are screened using CEDSS, which exhibit 17 times the ability to degrade collagen when compared to other cells. The degradation ability of dLSECs is mediated by the upregulation of MMP9. In particular, mRNA expression of MMP9 shows an 833‐fold increase in dLSECs compared to normal endothelial cells (nLSECs), and MMP9 is regulated by transcription factor c‐Fos. In vivo, single intrasplenic injection of dLSECs alleviates advanced liver fibrosis in mice, while intraperitoneal administration of liver‐targeting peptide‐modified dLSECs shows enhanced fibrosis‐targeting effects. Degradative human umbilical vein endothelial cells (dHUVECs) prove their enhanced potential of clinical translation. Together, these results highlight the potential of ECM‐degrading endothelial cells in alleviating advanced liver fibrosis, thus providing remarkable insights in the development of ECM‐targeting therapeutics.
Extracellular matrix (ECM) scar hinders the recovery from liver cirrhosis. Here, an in vitro cell‐mediated ECM‐degradation screening system (CEDSS) is developed and discovers a type of primed endothelial cells with exceptional ECM‐degradation ability (dLSECs) after high‐throughput screening. dLSECs can effectively breakdown collagen scar in vitro and in vivo through matrix metalloproteinase (MMP) expression, providing potential ECM‐targeting strategy for cirrhosis treatment.