Fig. 1 |. Initiation of fibrosis.

a, Onset of fibrosis upon epithelial injury. Both normal and fibrotic tissue repair typically start with an injury to the epithelial lining of organs, here exemplified by lung alveolar epithelium. Injury to epithelial cells (indicated by the lightning symbol) — for example, owing to genetic polymorphisms, autoimmune disease or exposure to environmental toxins — compromises tissue architecture and barrier function, which results in local mechanical stresses that arise from enhanced fluid flow and cell strain. Epithelial cell-derived injury signals activate local and circulating monocytes and/or macrophages (centre of the figure) and fibroblasts (left) into various repair phenotypes. Persistent crosstalk between such activated cells (curved arrows) can result in the formation of profibrotic niches that drive the fibrotic process. b, Fibroblastic cell activation states and functions. Mesenchymal cells with various homeostatic functions and locations in normal tissue are activated by tissue injury to contribute to acute repair by proliferating, migrating into the injury site and performing basic inflammatory functions. Either directly or by passing over these initial activation states (it is not currently clear which), activated matrix fibroblasts produce collagen extracellular matrix (ECM) to restore lost tissue architecture. The low traction forces of migrating fibroblasts lead to collagen fibre alignment and enhanced mechanical resistance of the scar ECM, resulting in the formation of actomyosin bundles. Initially, these so-called stress fibres are composed of cytoplasmic β- and γ-actins in contractile proto-myofibroblasts that further contribute to ECM remodelling and stiffening. With increasing ECM stiffness, proto-myofibroblast stress fibres progressively incorporate neoexpressed α-smooth muscle actin (αSMA), which confers even higher contractile activity to overcome higher ECM stiffness.