Tension-induced directional migration of hepatic stellate cells potentially coordinates liver fibrosis progression

Abstract

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.