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.
David Dolivo et al. recently shared their views regarding our study on in vitro primed endothelial cells, which were capable of degrading scars. The authors proposed that the current treatment strategy for fibrosis should be broadened to involve other cell types, stimuli, elements of the extracellular matrix (ECM) and targeted organ types. Transcriptomic profiles have been specified as an effective resource for predicting cells with the capability to degrade the ECM. The authors were also concerned if the ECMdegradation therapy for fibrosis would be accomplished in other organs (e.g., cardiac fibrosis), which did not possess the same regenerative capabilities as the liver. Overall, we found these comments quite inspiring for future endeavors in cell-degradation therapy in the treatment of fibrosis in multiple organs.As liver fibrosis advances, collagen I is the most prominent ECM component. [1] We centered our study on collagen I for construction of a cell-mediated ECM-degradation screening system (CEDSS), [2] whereas other ECM components such as fibronectin, elastin, and collagen III were absent. In the future, CEDSS needs to be further improved to tailor the concentration of collagen I, supplement with other ECM components, and include multiple ECM crosslinking schemes [3] (e.g., lysyl oxidases, transglutaminases, and advanced glycation end products) according to the characteristics of pathological ECM in different fibrotic organs. This would be more bionic and effective in screening fibrotic ECM degrading cells for specialized organs.Utilizing cell type-specific transcriptomic profiles to predict cells with the capacity to break down the extracellular matrix (ECM) is a noteworthy concept. For instance, by assessing the expression of proteases related to the ECM degradation of various cell types, we can identify potential ECM-degrading cells and related regulatory mechanisms. Nevertheless, omics data of transcriptomic profiles only reveal the expression of proteases at the gene level, thus the function of ECM degradation of the cells should still be determined and validated by functional assays based on CEDSS.
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