Intercellular communication between hepatic stellate cells and myofibroblasts mediated by osteopontin and FGF18 promotes liver fibrosis

Hepatic stellate cells (HSCs) play a central role in the development of liver fibrosis. We previously showed that fibroblast growth factor 18 (FGF18) promotes liver fibrosis by increasing HSC proliferation. However, the underlying mechanisms remain incompletely understood. Here, we showed that FGF18 efficiently induced osteopontin (<i>Spp1</i>/OPN) expression in culture-activated αSMA⁺ HSCs, but not in freshly prepared quiescent HSCs. Notably, OPN upregulated profibrotic genes only in quiescent HSCs, suggesting that the activation status of HSCs influences their responsiveness to FGF18 and OPN. Furthermore, FGF18 and TGFβ synergistically increased <i>Spp1/</i>OPN expression in culture-activated αSMA⁺ HSCs. Immunohistochemical analyses of murine liver fibrosis models revealed that OPN was expressed predominantly in αSMA⁺ myofibroblasts, but not in desmin⁺ quiescent HSCs. The cell-cell communication analyses further revealed that myofibroblast-derived <i>Spp1</i> signaled to HSCs in fibrotic livers. Together, FGF18 initiates a feedforward loop between quiescent and activated αSMA⁺ HSCs/myofibroblasts via OPN signaling, thereby driving fibrosis progression.