Fibroblasts are the primary cellular source responsible for synthesis and remodeling of the extracellular matrix (ECM). These cells are in communication with the surrounding microenvironment and play a key role in lung homoeostasis. Following lung injury, fibroblasts are activated and undergo myofibroblast differentiation. Myofibroblasts are key effector cells for lung repair following injury. In addition to fibroblasts, perivascular pericytes and mesenchymal stem cells (MSCs) of bone marrow (BM) origins contribute to myofibroblast population. There is evidence that type II alveolar epithelial cells can differentiate into myofibroblasts in vitro through a process known as epithelial–mesenchymal transition (EMT); however, the role of EMT in fibrogenesis in vivo remains controversial. Myofibroblasts express α-smooth muscle actin (α-SMA), develop robust actin filaments (stress fibers), and acquire contractile activity. The function and behavior of myofibroblasts are regulated by both biochemical and physical cues in the surrounding microenvironment. The fate of myofibroblasts is a key determinant of whether an injury–repair response will resolve or progress into fibrosis. Destruction and aberrant remodeling of the ECM is a common feature of many lung diseases, including pulmonary fibrosis, asthma, chronic obstructive pulmonary disease (COPD), and lung cancer. Targeting myofibroblasts and tissue remodeling may provide a novel and effective strategy for treating a number of chronic lung diseases.
Fibroblasts were described as early as in the late 19th century, based on their location and their microscopic appearance.1 These are elongated cells that display a spindle-shaped morphology with extended cell processes.2 Fibroblasts are ubiquitous in tissues and organs throughout the body and communicate with other cells such as epithelial cells (Fig. 28-1). Despite its discovery over a century, a reliable and specific molecular marker that identifies the fibroblast is currently lacking. Many indicators of fibroblast phenotype have been suggested in the previous studies (e.g., fibroblast-specific protein 1, vimentin, prolyl 4-hydroxylase, procollagen-Iα2, etc.).3 However, none of them are specific to fibroblasts and/or are present in all fibroblasts. Currently, fibroblasts are identified by their ability to adhere to plastic, and their lack of markers that indicate other cell lineages. Clearly, better cellular markers with absolute specificity for fibroblasts will aid in the study of sources, differentiation, and phenotypic plasticity of fibroblasts.
An interstitial fibroblast in the alveolar wall. A. A transmission electron microscopic image showing the structural organization of the alveolar wall in canine lung. Fb, fibroblast; Cp, capillary; AL, alveolar lumen; (B) summary of fibroblast (red) relationships with type I (green) and type II (purple) alveolar epithelial cells, capillary endothelial cells (yellow), and pericytes (orange) in human and rabbit alveolar walls. (Reproduced with permission from Burns AR, Smith CW, Walker DC. Unique structural features that influence neutrophil emigration into the lung. Physiol Rev. 2003;83(2):309–336.)
Tissue-Specific Fibroblasts and Fibroblast Heterogeneity