Increased expression and accumulation of GDF15 in IPF extracellular matrix contribute to fibrosis

Abstract

Idiopathic pulmonary fibrosis (IPF) is a chronic disease of unmet medical need. It is characterized by formation of scar tissue leading to a progressive and irreversible decline in lung function. IPF is associated with repeated injury, which may alter the composition of the extracellular matrix (ECM). Here, we demonstrate that IPF patient–derived pulmonary ECM drives profibrotic response in normal human lung fibroblasts (NHLF) in a 3D spheroid assay. Next, we reveal distinct alterations in composition of the diseased ECM, identifying potentially novel associations with IPF. Growth differentiation factor 15 (GDF15) was identified among the most significantly upregulated proteins in the IPF lung–derived ECM. In vivo, GDF15 neutralization in a bleomycin-induced lung fibrosis model led to significantly less fibrosis. In vitro, recombinant GDF15 (rGDF15) stimulated α smooth muscle actin (αSMA) expression in NHLF, and this was mediated by the activin receptor-like kinase 5 (ALK5) receptor. Furthermore, in the presence of rGDF15, the migration of NHLF in collagen gel was reduced. In addition, we observed a cell type–dependent effect of GDF15 on the expression of cell senescence markers. Our data suggest that GDF15 mediates lung fibrosis through fibroblast activation and differentiation, implicating a potential direct role of this matrix-associated cytokine in promoting aberrant cell responses in disease.

Retrospective identification of intrinsic factors that mark pluripotency potential in rare somatic cells

“…The other primary gene expression signature of primed fibroblasts we observed was lower expression of several genes associated with activated fibroblasts ( SPP1, SERPINE2, THBS1, TAGLN ) (Hsia et al, 2016; Layton et al, 2020; Peyser et al, 2019; Sandberg et al, 2019), differentiation into myofibroblasts ( MYL9, ACTA2, TPM2, POSTN ) (Guerrero-Juarez et al, 2019; Hsia et al, 2016; Layton et al, 2020; Walker et al, 2019), and pathological fibrosis ( GDF15, IGFBP7, GAS5 ) (L.-X. Liu et al, 2009; Radwanska et al, 2022; Tang et al, 2020)(Radwanska et al, 2022; Tang et al, 2020). This signature suggests that unactivated fibroblasts within the population are more likely to reprogram.…”

High-Throughput Extracellular Matrix Proteomics of Human Lungs Enabled by Photocleavable Surfactant and diaPASEF

“…Matrisome associated proteins enriched in the Azo fraction included Galectin-3 (gene: LGALS3), growth/differentiation factor 15 (gene: GDF15), and Chondroitin sulfate proteoglycan 4 (gene: CSPG4) (Figure F). Included in the proteins enriched in this fraction were four Galectin species (genes LGALS1, LGALS3, LGALS8, and LGALS9), which have been found to regulate transforming growth factor beta-1 pathways in idiopathic pulmonary fibrosis (IPF). , Growth factors associated with ECM synthesis and dysregulation in IPF , including growth/differentiation factor 15 (GDF15) and transforming growth factor beta-1 proprotein (TGFB1) were enriched in the Azo fraction. Additionally, proteoglycan-binding proteins such as Chondroitin sulfate proteoglycan 4 (CSPG4) were enriched in this fraction.…”

High-throughput Extracellular Matrix Proteomics of Human Lungs Enabled by Photocleavable Surfactant and diaPASEF

“…Included in the proteins enriched in this fraction were four Galectin species (genes LGALS1, LGALS3, LGALS8, and LGALS9), which have been found to regulate transforming growth factor beta-1 pathways in idiopathic pulmonary fibrosis (IPF). 41 Growth factors associated with ECM synthesis and dysregulation in IPF 42 including growth/differentiation factor 15 (GDF15) and transforming growth factor beta-1 proprotein (TGFB1) were enriched in the Azo fraction. Additionally, proteoglycan-binding proteins such as Chondroitin sulfate proteoglycan 4 (CSPG4) 43 were enriched in this fraction.…”