Cheng Lyu

Liver fibrosis is an over-reacted wound healing that becomes lethal in its late stage, when hepatic stellate cells (HSCs) trigger fibrotic response, proliferation of connective tissue and build-up of directional fibrous tissue bands (septa). Current in vitro models of liver fibrosis cannot reproduce liver lobule structure and the dynamic formation of septa at the same time, and the known biochemical cues underlying the progression of liver fibrosis cannot explain directional formation of fibrotic tissue. Here we report a microfabricated in vitro model that reproduces both the hexagonal liver lobule structure and the dynamic directionality of septa formation. By using collagen and primary mouse HSCs or human HSC lines, we found that tension was necessary to coordinate the cell migration that contributes to the band-like cell distribution and that HSCs sensed directional biophysical cues through liquid–liquid phase separation. This system allows the study of the biophysical interaction of HSCs and collagen during the formation of septa structures, and could be used to deepen our understanding of liver fibrosis progression.

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.