Principles of Cell Circuits for Tissue Repair and Fibrosis

Abstract

Tissue-repair is a protective response after injury, but repetitive or prolonged injury can lead to fibrosis, a pathological state of excessive scarring. To pinpoint the dynamic mechanisms underlying fibrosis, it is important to understand the principles of the cell circuits that carry out tissue-repair. In this study, we establish a cell-circuit framework for the myofibroblast-macrophage circuit in wound-healing, including the accumulation of scar-forming extracellular matrix. We find that fibrosis results from multi-stability between three outcomes, which we term 'hot fibrosis' characterized by many macrophages, 'cold fibrosis' lacking macrophages, and normal wound-healing. The cell-circuit framework clarifies several unexplained phenomena including the paradoxical effect of macrophage depletion, the limited time-window in which removing inflammation leads to healing, the effects of cellular senescence, and why scar maturation takes months. We define key parameters that control the transition from healing to fibrosis, which may serve as potential targets for therapeutic reduction of fibrosis.

A spatially restricted fibrotic niche in pulmonary fibrosis is sustained by M-CSF/M-CSFR signalling in monocyte-derived alveolar macrophages

“…Similar upregulation of CSF1R expression on fibrosis-associated macrophages can be found in the recent independent single-cell transcriptomic analysis of the lungs from patients with idiopathic pulmonary fibrosis, indicating high reproducibility of our findings [42]. Detection of Csf1/CSF1 expression in these alveolar macrophages suggests they can maintain their population in the fibrotic niche via autocrine production of M-CSF, thus becoming independent of signals from other resident lung cells for their survival as was recently postulated in an elegant computational model of fibrosis containing macrophages and fibroblasts [41,43]. We confirmed this hypothesis by showing two pharmacological strategies to inhibit CSF1 signalling reduced the number of monocyte-derived alveolar macrophages in the niche and reduced the severity of asbestos-induced fibrosis.…”

Resetting proteostasis with ISRIB prevents pulmonary fibrosis

“…We and others have shown that after recruitment these monocyte-derived alveolar macrophages form stable, perturbation-resistant circuits that drive fibroblast proliferation and matrix production (16)(17)(18). Over time these fibroblasts may gain the ability to maintain proliferation and matrix production independent of macrophages, leading to localized areas of unchecked fibrosis (43,44).…”

“…These kinases all phosphorylate eIF2a, a component of eukaryotic initiation factor 2 (eIF2), which is required to initiate translation on AUG start codons as a part of eIF2-GTP-Met-tRNA ternary complex. During translation initiation GTP is hydrolyzed to GDP, and a dedicated guanine nucleotide exchange factor for eIF2 (eIF2B) is needed to catalyze GDP-to-GTP exchange and reactivate eIF2 (44). Phosphorylation of eIF2a causes it to bind tightly to eIF2B precluding binding of the unphosphorylated protein and preventing binding to GTP (46).…”

“…We have shown that these monocyte-derived alveolar macrophages are maintained by autocrine or paracrine signaling via M-CSF/M-CSFR and localized specifically to regions of epithelial injury in close proximity to fibroblasts, inducing their activation, proliferation and secretion of matrix proteins (18). Over time, these regulatory circuits between macrophages and fibroblasts may become dispensable, creating autonomous regions of progressive fibrosis driven exclusively by fibroblasts (26,27). Even so, therapeutic strategies that reduce the ongoing recruitment of monocyte-derived alveolar macrophages and prevent the initiation of macrophage-fibroblast circuits are likely to be effective as the progression of the human disease is heterogenous in space and time.…”

Human library of cardiac promoters and enhancers

“…For example, transcription factors are involved in stress regulation of the adult heart that can result in hypertrophy, fibrosis, or ischemic injury 40,41 . Since the majority of the mechanisms work in opposition, an imbalance of the network of regulatory factors can lead to the pathogenesis of a disease.…”