Fibrotic extracellular matrix activates a profibrotic positive feedback loop

Abstract

Pathological remodeling of the extracellular matrix (ECM) by fibroblasts leads to organ failure. Development of idiopathic pulmonary fibrosis (IPF) is characterized by a progressive fibrotic scarring in the lung that ultimately leads to asphyxiation; however, the cascade of events that promote IPF are not well defined. Here, we examined how the interplay between the ECM and fibroblasts affects both the transcriptome and translatome by culturing primary fibroblasts generated from IPF patient lung tissue or nonfibrotic lung tissue on decellularized lung ECM from either IPF or control patients. Surprisingly, the origin of the ECM had a greater impact on gene expression than did cell origin, and differences in translational control were more prominent than alterations in transcriptional regulation. Strikingly, genes that were translationally activated by IPF-derived ECM were enriched for those encoding ECM proteins detected in IPF tissue. We determined that genes encoding IPF-associated ECM proteins are targets for miR-29, which was downregulated in fibroblasts grown on IPF-derived ECM, and baseline expression of ECM targets could be restored by overexpression of miR-29. Our data support a model in which fibroblasts are activated to pathologically remodel the ECM in IPF via a positive feedback loop between fibroblasts and aberrant ECM. Interrupting this loop may be a strategy for IPF treatment.

Lung Extracellular Matrix and Fibroblast Function

“…Newer data support the hypothesis that ECM stiffness in IPF promotes a profibrotic phenotype in fibroblasts, such as myofibroblast differentiation (4), matrix synthesis (22,32), and down-regulation of antifibrotic molecules (22). Indeed, recent data suggest that ECM protein translation in IPF is positively influenced by the IPF ECM, even in fibroblasts derived from normal donors (32). In line with these findings, a study now demonstrates that ECM within a physiologic range of stiffness is capable of reversing the activated myofibroblast phenotype (33), lending further credence to the idea that targeting ECM stiffness may be an appropriate therapeutic approach in fibrotic disorders.…”

“…Newer data support the hypothesis that ECM stiffness in IPF promotes a profibrotic phenotype in fibroblasts, such as myofibroblast differentiation (4), matrix synthesis (22,32), and down-regulation of antifibrotic molecules (22). Indeed, recent data suggest that ECM protein translation in IPF is positively influenced by the IPF ECM, even in fibroblasts derived from normal donors (32).…”

“…The effect of ECM on other progenitor cell types, such as bone marrow-derived stem cells or embryonic stem cells, is less clear. Coupled with evidence that fibrotic ECM drives further ECM protein translation (32), one must consider the possibility that MSCs used for lung repair may in fact be "hijacked" to develop a profibrotic phenotype. Early clinical studies suggest that bone marrow-derived MSC therapy is safe in patients with COPD (45), but, as mentioned previously, ECM stiffness may be markedly different between COPD and IPF lung.…”

Matrix, Mesenchyme, and Mechanotransduction

“…Several disease conditions in the lung are associated with progressive ECM deposition or destruction and corresponding alterations in lung mechanics, including idiopathic pulmonary fibrosis (IPF), in which progressive fibrotic scarring is associated with decreases in lung compliance (1,2), and emphysema, in which destruction of elastic fibers is associated with increases in compliance (3). Recent evidence indicates that alterations in the matrix may shift resident cell functions in ways that promote disease progression rather than homeostasis (4,5). Thus, signaling cues in the matrix, whether biochemical or biomechanical, can become part of the processes that promote disease progression, helping to account for the relentless progressive nature of lung dysfunction in chronic diseases and underscoring the need to understand the pathologic cues present in the matrix.…”

Therapeutic advances in idiopathic pulmonary fibrosis

“…Key mechanisms to switch off the healing response are in some way deficient and the accumulation of abnormal extracellular matrix may drive a profibrotic positive feedback loop resulting in the ongoing deposition of fibrotic tissue. [5][6][7][8] Until recently, the only real treatment options available were that of palliation, trial recruitment or referral for lung transplantation. The majority of earlier clinical trials utilised drugs with isolated molecular targets, such as tumour necrosis factor-α, interferon-γ and endothelin receptor inhibition, and met with failure; most probably because of the multitude of cellular processes that are involved in IPF pathogenesis.…”