A novel activation model for myofibroblasts derived from hepatic stellate cells in fibrotic liver

Myofibroblasts in liver fibrosis originate from the activation of hepatic stellate cells (HSCs). Traditional activation model contains high expression of α-SMA and COL1A1. Based on traditional model, collagen deposition in the fibrotic liver should constructed in the way of patchy distribution, which is not consistent with the objective situation. We analyzed the expression of α-SMA and COL1A1 in the cell subpopulation with myofibroblast characteristics based on the Single-cell sequencing database Omnibrowser, and the result showed that α-SMA and COL1A1 were negatively correlated. After inducing myofibroblast characteristics of HSCs using fibrotic serum, further intervention with TGF-β1 promotes the expression of α- SMA simultaneously inhibits COL1A1 expression. Multicolor fluorescence of rat fibrotic liver tissue showed a network-like distribution of TGF-β1, while COL1A1 showed a patchy distribution in the TGF-β1 loop. COL1A1 expression was lower near the TGF-β1 loop and higher in the distant region, presenting a centripetal pattern. The difference is that α-SMA expression was mostly concentrated next to the TGF-β1 loop. Therefore, we propose the dual mode transition model of myofibroblasts in fiber liver (DMTM model). In the DMTM model, myofibroblasts have dual modes. Myofibroblasts obtain enhanced migration ability, accompanied by inhibition of COL1A1 expression in the high-concentration region of TGF-β1. When migrating to the periphery of the TGF-positive region, myofibroblasts convert to a high collagen secretion phenotype. The combination of migration to the periphery and collagen secretion promotes the continuous spread of collagen bundles and ultimately forms the observed fiber distribution pattern in the fibrotic liver.