Fibroblast migration is essential to normal wound healing and pathological matrix
Fibroblast migration is essential to normal wound healing and pathological matrix deposition in fibrosis. 112) and position along developmental anterior-posterior and proximal-distal axes, as well as TKI-258 cost their dermal vs. nondermal sites of origin (99). These findings suggest that fibroblasts take up their relative positions in the body during development and are confined to relatively local domains thereafter, although one cannot altogether exclude local influences that plastically alter fibroblast characteristics. The spatial differences in fibroblast gene expression function as a source of positional memory for neighboring epithelial cells, engaging in reciprocal interactions to ensure appropriate patterning during wound healing or to maintain homeostasis (100). In addition to resident fibroblasts, there is also evidence that cells with fibroblast-like characteristics can be derived from circulating cells (34) TKI-258 cost and from epithelial and endothelial sources (56, 118), particularly in disease or wound-healing contexts. However, there is strong evidence that locally derived resident mesenchymal cells are activated to proliferate and migrate during wound healing or fibrosis and that such locally derived cells play an important role in these processes (45, 48, 101, 118, 121). Thus understanding how fibroblasts navigate the extracellular matrix in their local tissue environment is a major question relevant to Rabbit Polyclonal to API-5 understanding injury responses, regenerative healing, and fibrosis. In additional to spatial variations in gene expression, fibroblasts also exist along a differentiation continuum, and populations of cells likely include a variety of subclassifications. The best known of these is the myofibroblast, which is classically defined by the expression of the contractile protein -smooth muscle actin (45). Definitive markers to positively identify and subclassify fibroblasts remain elusive, hence they are often defined by their absence of other definitive markers along with the presence of relatively nonspecific markers, such as vimentin and S100a4 (FSP-1) (114). More definitive insight into fibroblast heterogeneity and TKI-258 cost origin should come from lineage tracing studies (98), which are already identifying fibroblast subpopulations important in injury repair and fibrosis (18, 101). Despite the variations in fibroblast subpopulations and the subtle differences in fibroblasts isolated from various organs and tissues, these cells exhibit many overriding similarities in appearance and function and are often studied interchangeably from across different tissues and sites of interest. Fibroblasts are easily isolated and grown in culture from many tissues, and the spontaneously immortalized 3T3 fibroblast cell line, originally derived from mouse embryo (120), is widely used in basic cell biology studies. Thus there is a long history of using cultured fibroblasts for routine investigation of cell and molecular biology, in particular their motile behaviors (e.g., Refs. 1, 2, 10, 41, 119, 123, 124). More recently, it has become apparent that the study of these cells in the artificial environment of the rigid 2D culture dish may strongly influence important behaviors of these cells and fail to capture some important aspects of how these cells behave within the tissues of the human body (27), echoing concepts first explored more than 30 years ago (9, 23, 40). This review highlights the differences in fibroblast function that emerge across extracellular matrices spanning simple (2D) to intact tissue matrices, using migration as widely studied and physiologically critical focus that illuminates the important interactions between the fibroblast and the extracellular matrix environment. Fibroblast Migration in Two Dimensions Although fibroblasts reside throughout many tissues of the human body, they still must be capable of motile function to fulfill their roles in tissue homeostasis and wound repair, traversing local tissue environments as needed to degrade, repair, or remodel the extracellular matrix. In standard cell culture approaches, fibroblasts are grown on 2D surfaces, typically glass or plastic, with surfaces modified to encourage cell and protein attachment. Such an arrangement is optimal for a number of microscopic imaging techniques, allowing cells to be visualized and followed over time as they migrate, either spontaneously or in response to chemotactic gradients or other biochemical stimuli that perturb motility. However, TKI-258 cost such settings also impose nonphysiological constraints, restricting cell spreading and movement to an artificially flat 2D surface. Nevertheless, such systems proved instrumental in developing current concepts for understanding.