Genesis of the myofibroblast in lung injury and fibrosis

Abstract

Tissue injury incites a repair response with a key mesenchymal component that provides the essential connective tissue for subsequent regeneration or pathological fibrosis. The fibroblast is the major mesenchymal cell type to be implicated in this connective tissue response, and it is in its activated or differentiated form that it participates in the repair process. The myofibroblast represents such an activated mesenchymal cell and is a key source of extracellular matrix and inflammatory/fibrogenic cytokines as well as participating in wound contraction. Although successful healing results in gradual disappearance of myofibroblasts, their persistence is associated with chronic and progressive fibrosis. Thus, elucidation of the mechanism involved in the genesis of the myofibroblast should provide insight into both pathogenesis of chronic fibrotic diseases and therapeutic strategies for their management and control. Although the fibroblast is a well-documented progenitor cell for the myofibroblast, recent studies have suggested additional precursor cells that have the potential to give rise to the myofibroblast. Many of the studies focused on mechanisms and factors that regulate induction of α-smooth muscle actin expression, a key and commonly used marker of the myofibroblast. These reveal complex and multifactorial mechanisms involving transcriptional and epigenetic regulation and implicating diverse cell-signaling pathways, including those activated by the potent fibrogenic cytokine transforming growth factor β. Despite these extensive studies, many aspects remain poorly understood, with the suggestion that additional novel mechanisms remain to be discovered. Future studies with the help of newly developed technical advancements should expedite discovery in this direction.

Figure 1.

Myofibroblast precursors. Bone marrow–derived precursors for the fibrocyte and endothelial cell are presumably the hematopoietic stem cell and endothelial progenitor cell, respectively. Origination of epithelial cells from bone marrow precursors is controversial and indicated with a question mark. It is unclear at this time whether endothelial (endoMT) and epithelial–mesenchymal transition (EMT) could bypass the fibroblast stage and directly assume the myofibroblast phenotype. Other local mesenchymal progenitor cells (MPC) are also shown for completeness, but their specific identity is unclear and poorly defined.