Host Responses in Tissue Repair and Fibrosis

Abstract

Myofibroblasts accumulate in the spaces between organ structures and produce extracellular matrix (ECM) proteins, including collagen I. They are the primary “effector” cells in tissue remodeling and fibrosis. Previously, leukocyte progenitors termed fibrocytes and myofibroblasts generated from epithelial cells through epithelial-to-mesenchymal transition (EMT) were considered the primary sources of ECM-producing myofibroblasts in injured tissues. However, genetic fate mapping experiments suggest that mesenchyme-derived cells, known as resident fibroblasts, and pericytes are the primary precursors of scar-forming myofibroblasts, whereas epithelial cells, endothelial cells, and myeloid leukocytes contribute to fibrogenesis predominantly by producing key fibrogenic cytokines and by promoting cell-to-cell communication. Numerous cytokines derived from T cells, macrophages, and other myeloid cell populations are important drivers of myofibroblast differentiation. Monocyte-derived cell populations are key regulators of the fibrotic process: They act as a brake on the processes driving fibrogenesis, and they dismantle and degrade established fibrosis. We discuss the origins, modes of activation, and fate of myofibroblasts in various important fibrotic diseases and describe how manipulation of macrophage activation could help ameliorate fibrosis.

Lung Pericytes and Resident Fibroblasts

“…However, the TGF-b pathway is so broadly engaged in development and pathogenesis in all organs, including its potential to stimulate opposing effects in angiogenesis, that without data from inducible, cell typee specific inhibition experiments, it remains problematic to assign discrete, TGF-bedependent roles to lung pericytes in vascular biology. 3,5,18,53 Pericytes sense vasoactive molecules and neurotransmitters, and one of their first proposed functions was to control blood flow by regulating the diameter of capillary vessels. 3 Ang-1 overexpression did increase capillary diameter, although whether periyctes could exert sufficient mechanical force to squeeze or stretch a capillary structure has been debated.…”

“…Activation of the NLRP3 inflammasome to produce IL-1b is one of the strongest defenses against infections, but can also severely damage tissue and plays a highly pathogenic role in lung fibrosis. 53,64 Toll-like receptor-2 and Clec7a (Dectin-1) detect microbial molecular signatures, but also may react to host-derived ligands generated by cellular damage. 65 Oncostatin-M (OSM), an IL-6 family cytokine, has been strongly implicated in allergic and fibrotic lung diseases and stimulates endothelial, smooth muscle, fibroblast, leukocyte, and epithelial cells from the lung in synergy with other inflammatory cytokines.…”

“…67 Pericytes expressing immune surveillance and effector genes may therefore function in roles traditionally envisioned for macrophages. 6,53,58,64,68 Indeed, most of the immunological genes and functions identified in pericytes were long since recognized and still most commonly studied in monocytes and macrophages. 10,23,53,58,62 Distinctions between resident tissue macrophages and macrophages differentiating from immigrating monocytes have recently become far better appreciated.…”

“…6,53,58,64,68 Indeed, most of the immunological genes and functions identified in pericytes were long since recognized and still most commonly studied in monocytes and macrophages. 10,23,53,58,62 Distinctions between resident tissue macrophages and macrophages differentiating from immigrating monocytes have recently become far better appreciated. Resident tissue macrophages have unexpectedly but commonly been found to react with low sensitivity to signals from microbes or damage, and to respond without producing high levels of proinflammatory and profibrotic cytokines.…”

Ubiquitin C-terminal hydrolase 1: A novel functional marker for liver myofibroblasts and a therapeutic target in chronic liver disease

“…Fibrosis has many similarities to cancer including alterations in cell phenotype and dysregulation of the cell cycle, which promotes the proliferation of myofibroblasts and spread of fibrosis [24][25][26]. Hence, it is surprising that to date there has been little attention focused on the Ub system and its regulators in fibrosis.…”