Mechanotransduction-modulated fibrotic microniches reveal the contribution of angiogenesis in liver fibrosis

Abstract

The role of pathological angiogenesis on liver fibrogenesis is still unknown. Here, we developed fibrotic microniches (FμNs) that recapitulate the interaction of liver sinusoid endothelial cells (LSECs) and hepatic stellate cells (HSCs). We investigated how the mechanical properties of their substrates affect the formation of capillary-like structures and how they relate to the progression of angiogenesis during liver fibrosis. Differences in cell response in the FμNs were synonymous of the early and late stages of liver fibrosis. The stiffness of the early-stage FμNs was significantly elevated due to condensation of collagen fibrils induced by angiogenesis, and led to activation of HSCs by LSECs. We utilized these FμNs to understand the response to anti-angiogenic drugs, and it was evident that these drugs were effective only for early-stage liver fibrosis in vitro and in an in vivo mouse model of liver fibrosis. Late-stage liver fibrosis was not reversed following treatment with anti-angiogenic drugs but rather with inhibitors of collagen condensation. Our work reveals stage-specific angiogenesis-induced liver fibrogenesis via a previously unrevealed mechanotransduction mechanism which may offer precise intervention strategies targeting stage-specific disease progression.

Curcumol attenuates liver sinusoidal endothelial cell angiogenesis via regulating Glis‐PROX1‐HIF‐1α in liver fibrosis

“…Primary LSECs almost pursued to lose their fenestrae out of normal environment regardless of the slight effect of curcumol in vitro. The process of hepatic angiogenesis is divided into many stages, and the effects of drug therapy on angiogenesis at different stages are also different . LSEC renewal differs in physiological and in pathological conditions .…”

“…All these processes are regulated by the hypoxia‐inducible factor‐1α (HIF‐1α) . Basic and clinical research also showed that inhibition of LSEC angiogenesis and HSC paracrine effects could alleviate liver fibrosis …”

Too Stiff, Too Late . . . Timing Is Everything in Antiangiogenic Treatment of Liver Fibrosis

“…To prove this concept, the authors analyzed the mRNA profiles of LSECs at an early and a late stage of fibrosis. Indeed, mechanobiologically modulated LSECs in microfibrotic niches largely recapitulated the featured mRNA changes of LSECs during fibrosis progression in vivo . On a functional level, the authors observed that HSC activation was increased in early‐stage compared to late‐stage fibrosis.…”

“…A recent publication in Nature Materials by Liu and colleagues investigated the role of mechanical tension generated during angiogenesis and its influence on the progression of liver fibrosis . For the purpose of this study, the authors developed a novel in vitro tool to study the interaction between liver sinusoidal endothelial cells (LSECs) and hepatic stellate cells (HSCs).…”

“…The study by Liu et al enlightens the stage‐dependent role of angiogenesis and angiogenesis‐induced activation of HSCs from a mechanobiological perspective . Using a novel in vitro tool (microfibrotic niche), the authors reveal mechanotransduction as an important pathway in liver fibrosis progression.…”