Transcriptional and spatial profiling of fibroblasts from human lungs highlights CTHRC1+ cells as fibrogenic signaling hubs in fibrosis

Samples were collected from IPF upper lobe, IPF lower lobe, and age-matched control lung tissue and processed using the 10x Genomics Chromium platform. Unsupervised clustering identified six transcriptionally distinct mesenchymal subtypes — alveolar, adventitial, inflammatory, CTHRC1⁺, peribronchial and smooth muscle cell — across conditions.

Differential gene expression, pathway enrichment, and cell-cell communication analyses were performed to characterize subtype-specific transcriptional programs, ECM remodeling signatures, and intercellular signaling networks in the fibrotic lung niche. CTHRC1⁺ fibroblasts emerged as a dominant fibrogenic hub in IPF, characterized by elevated fibrillar collagen expression, broad outgoing signaling through collagen, fibronectin, and periostin pathways, and spatial co-localization with fibroblastic foci.