Myofibroblast differentiation and survival in fibrotic disease

Abstract

During wound healing, contractile fibroblasts called myofibroblasts regulate the formation and contraction of granulation tissue; however, pathological and persistent myofibroblast activation, such as occurs in hypertrophic scars or tissue fibrosis, results in loss of function. Many outstanding reviews outline cellular and molecular features of myofibroblasts, and their roles in a variety of diseases. This review will focus on the origins of myofibroblasts and the factors which control their differentiation and prolonged survival in fibrotic tissues. Pulmonary fibrosis is used to illustrate many key points, but examples from other tissues and models are also included. Myofibroblasts emerge mostly from tissue-resident fibroblasts but also from epithelial, endothelial cells or other mesenchymal precursors. Their differentiation is influenced by cytokines, growth factors, extracellular matrix composition and stiffness, and cell surface molecules such as proteoglycans and THY1, among other factors. Many of these effects are modulated by cell contraction. Myofibroblasts resist programmed cell death, promoting their accumulation in fibrotic tissues. The cause of resistance to apoptosis in myofibroblasts is under ongoing investigation, but many of the same stimuli that regulate their differentiation are involved. The contributions of oxidative stress, the WNT - β-catenin pathway and PPARγ to myofibroblast differentiation and survival are increasingly appreciated.

Matrix Stiffening and β1 Integrin Drive Subtype-Specific Fibroblast Accumulation in Lung Cancer

“…Moreover, the effect of matrix stiffening on fibroblast density was dominant or comparable with that due to mitogenic cues present in serum up to 0.5% FBS, which is a more physiologic concentration than the 10% to 20% FBS used in many cell culture studies. All these findings strongly support that matrix stiffening alone may be as important as soluble growth factors in driving fibroblast accumulation in vivo, thereby challenging the current view of stromagenesis as driven by paracrine signaling only (3,(8)(9)(10). Moreover, they extend previous evidence of a positive feedback loop in which activated fibroblasts lay out increased amounts of fibrotic ECM components that render a stiffer ECM, which in turn may drive fibroblast activation and accumulation further (11,14).…”

“…The current paradigm of TAF accumulation based on repairlike processes (3,(8)(9)(10)) supports a therapeutic strategy to reduce their density based on inhibiting stromal growth factors. Our data support the latter strategy in ADC-TAFs but not in SCC-TAFs.…”

“…In NSCLC and other cancer types, TAFs are frequently found in an activated/myofibroblastlike phenotype that is roughly characterized by the expression of alpha-smooth muscle actin (a-SMA) and the enhanced deposition of fibrotic ECM components. In the current paradigm, TAF accumulation is assumed to be largely driven by paracrine signals secreted by cancer cells or infiltrated immune cells as in generic repair processes (3,(8)(9)(10). However, two lines of evidence suggest that mechanical cues provided by the abnormal tissue hardening of desmoplastic tumors may also contribute to TAF accumulation.…”

Therapeutic Targeting of Src Kinase in Myofibroblast Differentiation and Pulmonary Fibrosis

“…These functions of myofibroblasts expedite wound closure during normal wound healing (Gabbiani et al, 1971). Although myofibroblasts facilitate wound healing, they also contribute to the development of fibrotic disorders in multiple organs, such as in the progressive fibrotic lung disease, idiopathic pulmonary fibrosis (IPF) (Hinz et al, 2007;Ding et al, 2011;Kis et al, 2011;Ley et al, 2011). It is important to fully understand the mechanisms involved because therapeutic targeting of key signaling pathways regulating myofibroblast differentiation and activation may reduce the progression of fibrotic disorders, such as IPF.…”

Glycolytic Reprogramming in Myofibroblast Differentiation and Lung Fibrosis

“…A defining feature of idiopathic pulmonary fibrosis (IPF) and other progressive fibrotic pathologies is the activation and persevering presence of tissue myofibroblasts (myo-Fbs) (8)(9)(10)(11)(12)(13). Myo-Fbs are characterized by de novo expression of smooth muscle actin (SMA)-a; formation of stress fibers; and enhanced abilities to migrate, contract, and produce extracellular matrix (14)(15)(16).…”