Identification of a Cell-of-Origin for Fibroblasts Comprising the Fibrotic Reticulum in Idiopathic Pulmonary Fibrosis

Abstract

Idiopathic pulmonary fibrosis (IPF) is a progressive disease of the middle aged and elderly with a prevalence of one million persons worldwide. The fibrosis spreads from affected alveoli into contiguous alveoli, creating a reticular network that leads to death by asphyxiation. Lung fibroblasts from patients with IPF have phenotypic hallmarks, distinguishing them from their normal counterparts: pathologically activated Akt signaling axis, increased collagen and α-smooth muscle actin expression, distinct gene expression profile, and ability to form fibrotic lesions in model organisms. Despite the centrality of these fibroblasts in disease pathogenesis, their origin remains uncertain. Here, we report the identification of cells in the lungs of patients with IPF with the properties of mesenchymal progenitors. In contrast to progenitors isolated from nonfibrotic lungs, IPF mesenchymal progenitor cells produce daughter cells manifesting the full spectrum of IPF hallmarks, including the ability to form fibrotic lesions in zebrafish embryos and mouse lungs, and a transcriptional profile reflecting these properties. Morphological analysis of IPF lung tissue revealed that mesenchymal progenitor cells and cells with the characteristics of their progeny comprised the fibrotic reticulum. These data establish that the lungs of patients with IPF contain pathological mesenchymal progenitor cells that are cells of origin for fibrosis-mediating fibroblasts. These fibrogenic mesenchymal progenitors and their progeny represent an unexplored target for novel therapies to interdict fibrosis.

Calcium-binding protein S100A4 confers mesenchymal progenitor cell fibrogenicity in idiopathic pulmonary fibrosis

“…Gene expression profiling of IPF MPCs distinguished them from MPCs isolated in a similar manner from the lungs of patient controls, with enrichment of genes associated with diseaserelevant ontologies (14). Specifically, we found that IPF MPCs express higher levels of S100A4 compared with control MPCs (14).…”

“…Specifically, we found that IPF MPCs express higher levels of S100A4 compared with control MPCs (14). S100A4, a calcium binding protein, is upregulated in cancer stem cells, where it controls proliferation, differentiation, and metastasis (15)(16)(17)(18)(19)(20)(21)(22).…”

“…While the reason for the variation in size and shape are unclear, one possible explanation is that there is temporal growth of fibroblastic foci as the fibrotic lesions evolve due to the spread of fibrosis into adjacent normal alveolar structures. Our prior studies revealed a distinct IPF fibroblast phenotype characterized by aberrant integrin signaling, leading to pathological activation of proliferation and survival pathways (11)(12)(13); they also revealed that IPF lung harbors pathologic mesenchymal progenitor cells (MPCs) that are cells of origin for IPF fibroblasts (14). However, the mechanism(s) underlying IPF MPC fibrogenicity and their role in the stereotypic progression of fibrosis are not known.…”

“…(A) Genome-wide RNA sequencing data. Shown is the heatmap for S100A4 gene expression in IPF and control MPCs derived from 3 IPF patients and 3 control patients based on our previously published data (14). Colors represent per gene Z score (expression difference normalized for standard deviation).…”

“…We previously discovered that IPF lung tissue harbors pathologic MPCs that are cells of origin for IPF fibroblasts (14); however, the molecular mechanisms underlying their fibrogenicity remain undefined. To identify molecular processes that might impart IPF Idiopathic pulmonary fibrosis (IPF) is a progressive disease with a prevalence of 1 million persons worldwide.…”