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

Abstract

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.

Comment on “Scar‐Degrading Endothelial Cells as a Treatment for Advanced Liver Fibrosis”

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We recently read Zhao et al [1] with great interest. In this report, the authors describe a unique and intriguing method to screen for cells with substantial collagenase activity, followed by extensive characterization of these cells' ability to degrade fibrotic extracellular matrix (ECM) in a murine model in vivo and in human samples ex vivo.

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“…[2] Therefore, the need for therapeutic modalities to prevent and treat fibrosis is paramount, though success in clinical translation of antifibrotic pharmacologic therapies has been disappointing. Another potential treatment strategy is to deliver therapeutic cells, but this is complicated by the challenge of selecting appropriate cells with the potential to prevent or reverse fibrosis, as well as to deliver these cells effectively and efficiently to the tissue of interest.In Zhao et al, [1] the authors aimed to select a source of cells with a high degree of collagenase activity to be used as a cellular therapy to degrade liver collagen in an advanced stage hepatic fibrosis model in vivo. The authors initially performed a high-throughput screen for collagenase activity by seeding various preparations of cells into a collagen matrix pretagged with rhodamine, such that fluorescence of the culture supernatant could be used as a proxy for collagenase activity.…”

“…In Zhao et al., [ 1 ] the authors aimed to select a source of cells with a high degree of collagenase activity to be used as a cellular therapy to degrade liver collagen in an advanced stage hepatic fibrosis model in vivo. The authors initially performed a high‐throughput screen for collagenase activity by seeding various preparations of cells into a collagen matrix pretagged with rhodamine, such that fluorescence of the culture supernatant could be used as a proxy for collagenase activity.…”

Response to a Comment on “Scar‐Degrading Endothelial Cells as a Treatment for Advanced Liver Fibrosis”

“…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.…”

“…Meanwhile, controlling the degradation degree of the pathological ECM is a key safety concern that must be taken into account when performing clinical treatment, as it is necessary to ensure that any excess ECM is degraded without damaging the function of the tissue. To avoid ECM breakdown in nonfibrotic organs and tissues, targeted delivery of cells should be imperative, which can be accomplished by modifying the cell membrane with organ‐targeting peptides [ 2 ] or employing a mechanoresponsive cell system (MRCS). [ 16 ]…”