Myofibroblasts revert to an inactive phenotype during regression of liver fibrosis

TLDR

Myofibroblasts derived from hepatic stellate cells drive fibrous scar formation in liver fibrosis, yet fibrosis can regress and these cells disappear when the injurious stimulus is removed. The study aims to determine whether myofibroblasts can revert to an inactive phenotype during fibrosis regression. The authors used Cre‑LoxP genetic labeling to track hepatic stellate cells/myofibroblasts during recovery from CCl₄‑ and alcohol‑induced fibrosis. During regression, about half of myofibroblasts survive apoptosis, down‑regulate fibrogenic genes, and adopt a distinct inactive phenotype that can rapidly reactivate and drive fibrosis, a process linked to up‑regulation of anti‑apoptotic Hspa1a/b.

Abstract

Myofibroblasts produce the fibrous scar in hepatic fibrosis. In the carbon tetrachloride (CCl(4)) model of liver fibrosis, quiescent hepatic stellate cells (HSC) are activated to become myofibroblasts. When the underlying etiological agent is removed, clinical and experimental fibrosis undergoes a remarkable regression with complete disappearance of these myofibroblasts. Although some myofibroblasts apoptose, it is unknown whether other myofibroblasts may revert to an inactive phenotype during regression of fibrosis. We elucidated the fate of HSCs/myofibroblasts during recovery from CCl(4)- and alcohol-induced liver fibrosis using Cre-LoxP-based genetic labeling of myofibroblasts. Here we demonstrate that half of the myofibroblasts escape apoptosis during regression of liver fibrosis, down-regulate fibrogenic genes, and acquire a phenotype similar to, but distinct from, quiescent HSCs in their ability to more rapidly reactivate into myofibroblasts in response to fibrogenic stimuli and strongly contribute to liver fibrosis. Inactivation of HSCs was associated with up-regulation of the anti-apoptotic genes Hspa1a/b, which participate in the survival of HSCs in culture and in vivo.