GDF15 is an epithelial-derived biomarker of idiopathic pulmonary fibrosis

Abstract

Idiopathic pulmonary fibrosis (IPF) is the most common and devastating of the interstitial lung diseases. Epithelial dysfunction is thought to play a prominent role in disease pathology, and we sought to characterize secreted signals that may contribute to disease pathology. Transcriptional profiling of senescent type II alveolar epithelial cells from mice with epithelial-specific telomere dysfunction identified the transforming growth factor-β family member, growth and differentiation factor 15 (Gdf15), as the most significantly upregulated secreted protein. Gdf15 expression is induced in response to telomere dysfunction and bleomycin challenge in mice. Gdf15 mRNA is expressed by lung epithelial cells, and protein can be detected in peripheral blood and bronchoalveolar lavage following bleomycin challenge in mice. In patients with IPF, GDF15 mRNA expression in lung tissue is significantly increased and correlates with pulmonary function. Single-cell RNA sequencing of human lungs identifies epithelial cells as the primary source of GDF15, and circulating concentrations of GDF15 are markedly elevated and correlate with disease severity and survival in multiple independent cohorts. Our findings suggest that GDF15 is an epithelial-derived secreted protein that may be a useful biomarker of epithelial stress and identifies IPF patients with poor outcomes.

Single-cell RNA-seq reveals ectopic and aberrant lung-resident cell populations in idiopathic pulmonary fibrosis

“…These cells express markers of epithelial-mesenchymal transition (EMT) such as VIM, CDH2, FN1, COL1A1, TNC, and HMGA2 ( 10 ), senescence-related genes including CDKN1A, CDKN2A, CCND1, CCND2, MDM2, and GDF15 ( Fig. 2C , right) ( 11 , 12 ), and the highest normalized expression levels across all profiled cell types of established IPF-related molecules, such as matrix metallopeptidase 7 (MMP7) ( 13 ), combined with α V β 6 integrin subunits ( 14 ) and EPHB2 ( 15 ). When assessed by transcription factor motif enrichment, the cells exhibit high levels of expression and evidence of downstream activation of SOX9 ( Fig.…”

“…Third, these cells seem to be undergoing EMT, they express mesenchymal markers (COL1A1, CDH2, and HMGA2) and have lost the expression MIR205HG, a gene containing mir-205 and a gatekeeper against EMT ( 28 ). Fourth, they express multiple markers of senescence (CDKN1A, CDKN2A, MDM2, and GDF15) ( 11 , 12 ). Last, these cells are the highest expressers of genes implicated in the pathogenesis of IPF such as AVB6 ( 14 ), MMP7 ( 13 ), GDF15 ( 12 ), and EPHB2 ( 15 ).…”

“…Fourth, they express multiple markers of senescence (CDKN1A, CDKN2A, MDM2, and GDF15) ( 11 , 12 ). Last, these cells are the highest expressers of genes implicated in the pathogenesis of IPF such as AVB6 ( 14 ), MMP7 ( 13 ), GDF15 ( 12 ), and EPHB2 ( 15 ). Anatomically, these cells localize to a highly enigmatic region in the IPF lung at the active edge of the myofibroblast foci as we have demonstrated using a combination of markers including p16 (CDKN2A), p21 (CDKN1A), HMGA2, COX2 (PTGS2), p63(TP63), and KRT17.…”

Airway Basal Cells show a dedifferentiated KRT17highPhenotype and promote Fibrosis in Idiopathic Pulmonary Fibrosis

“…However, amphiregulin has been most consistently shown profibrotic effects in models of liver, kidney and heart fibrosis [37][38][39][40] . In the lung, amphiregulin was proposed as a mediator of TGFB1 mediated pulmonary fibrosis in the triple transgenic mouse model 41 2), markers of epithelial cells senescence such as GDF15 45 , and the EGFR ligands AREG and HBEGF in IPF-ABCs. Thus, the transcriptional phenotype of IPF-ABCs may represent the end results of the lung response to repetitive epithelial injuries 46 , which trigger exaggerated repair processes including dedifferentiation and epithelial-mesenchymal crosstalk 6,47 .…”

Growth Differentiation Factor 15 Ameliorates Anti-Glomerular Basement Membrane Glomerulonephritis in Mice

“…In general, GDF15 is believed to be associated with stress responses, but its precise biological functions remain to be elucidated. Although GDF15 has been shown to affect aspects of chronic diseases (both inflammation and fibrosis), whether it controls glomerular disease progression is unclear [ 31 , 33 , 34 ].…”