Resolution of organ fibrosis

Abstract

Fibrosis is the excessive accumulation of extracellular matrix that often occurs as a wound healing response to repeated or chronic tissue injury, and may lead to the disruption of organ architecture and loss of function. Although fibrosis was previously thought to be irreversible, recent evidence indicates that certain circumstances permit the resolution of fibrosis when the underlying causes of injury are eradicated. The mechanism of fibrosis resolution encompasses degradation of the fibrotic extracellular matrix as well as elimination of fibrogenic myofibroblasts through their adaptation of various cell fates, including apoptosis, senescence, dedifferentiation, and reprogramming. In this Review, we discuss the present knowledge and gaps in our understanding of how matrix degradation is regulated and how myofibroblast cell fates can be manipulated, areas that may identify potential therapeutic approaches for fibrosis.

Figure 1. Transdifferentiation of precursor cells into fibrogenic myofibroblasts.

Upon parenchymal injury, the wound-healing response leads to the release of fibrogenic growth factors and cytokines, the most prominent of which is TGF-β1. These factors drive the transdifferentiation and proliferation of precursor cells into myofibroblasts. Major precursors of myofibroblasts are cells of mesenchymal origin, including resident fibroblasts, pericytes, and Gli⁺ mesenchymal stem cell–like (MSC-like) cells. In some cases, myofibroblasts may be derived from bone marrow–derived (BM-derived) fibrocytes or through mesothelial-to-mesenchymal transition (MMT). Myofibroblasts produce ECM comprising fibrillar collagens that undergo extensive cross-linking and EDA-fibronectin, which promotes TGF-β1–induced transdifferentiation.

Figure 2. Fate of myofibroblasts during fibrosis resolution.

Fibrogenic myofibroblasts can be eliminated during fibrosis resolution through one of several alternative cell fates: apoptosis, senescence, and dedifferentiation. Cellular lineage reprogramming also serves as an alternative route to eliminate myofibroblasts. These cell fates are not mutually exclusive and can be driven through genetic or pharmacological manipulations to promote fibrosis resolution.