Novel approaches to target fibroblast mechanotransduction in fibroproliferative diseases

The ability of cells to sense and respond to changes in mechanical environment is vital in conditions of organ in-jury when the architecture of normal tissues is disturbed or lost. Among the various cellular players that respond to injury, fibroblasts take center stage in re-establishing tissue integrity by secreting and organizing extracellular matrix into stabilizing scar tissue. Activation, activity, survival, and death of scar-forming fibroblasts are tightly controlled by mechanical environment and proper mechanotransduction ensures that fibroblast activities cease after completion of the tissue repair process. Conversely, dysregulated mechanotransduction often results in fibroblast over-activation or persistence beyond the state of normal repair. The resulting pathological accumu-lation of extracellular matrix is called fibrosis, a condition that has been associated with over 40% of all deaths in the industrialized countries. Consequently, elements in fibroblast mechanotransduction are scrutinized for their suitability as anti-fibrotic therapeutic targets. We review the current knowledge on mechanically relevant factors in the fibroblast extracellular environment, cell-matrix and cell-cell adhesion structures, stretch-activated mem-brane channels, stress-regulated cytoskeletal structures, and co-transcription factors. We critically discuss the targetability of these elements in therapeutic approaches and their progress in pre-clinical and/or clinical trials to treat organ fibrosis.(c) 2023 Elsevier Inc. All rights reserved.

Automated summary

The ability of cells to sense and respond to mechanical changes is crucial in tissue injury and fibrosis. Fibroblasts play a central role in tissue repair by regulating extracellular matrix secretion and organization. Dysregulated mechanotransduction can lead to fibrosis, and targeting the elements involved in fibroblast mechanotransduction may be a potential therapeutic approach.