Fibroblast Activation / Myofibroblast

Fibroblasts are the quintessential supporting cell type, present in all tissues, where their shared core function is production of the extracellular matrix. On tissue damage they are among the first responders, undergoing a series of changes collectively called activation: increased proliferation and migration, and acquisition of a secretory and contractile phenotype, the myofibroblast, which is the farthest transcriptional and functional point from the quiescent homeostatic fibroblast.

Activation is driven both mechanically and by soluble signals. Mechanical stress pulls on the large latent complexes that hold TGF-beta inactive in the matrix, releasing active TGF-beta that induces the myofibroblast transition; alpha-smooth muscle actin-dependent contractility then creates a positive feedback loop amplifying the fibrotic cycle. Soluble activators include pathogen- and damage-associated molecular patterns, cytokines such as IL-6, IL-11, IL-13, IL-21 and TGF-beta1, chemokines such as MCP-1 and MIP-1alpha/beta, VEGF and PDGF, many supplied by immune cells or by fibroblasts themselves as autocrine feedback.

Myofibroblasts can revert to quiescence if an injury resolves in time, but under chronic insult they enter a self-sustaining cycle of irreversible scarring, or fibrosis. Fibroblast activation is also part of physiological aging, sometimes termed inflammaging, in which older tissue is enriched for activated fibroblasts secreting pro- and anti-inflammatory cytokines and tissue repair is impaired.