Identification of a cell-of-origin for fibroblasts comprising the fibrotic reticulum in idiopathic pulmonary fibrosis.

TitleIdentification of a cell-of-origin for fibroblasts comprising the fibrotic reticulum in idiopathic pulmonary fibrosis.
Publication TypeJournal Article
Year of Publication2014
AuthorsXia H, Bodempudi V, Benyumov A, Hergert P, Tank D, Herrera J, Braziunas J, Larsson O, Parker M, Rossi D, Smith K, Peterson M, Limper A, Jessurun J, Connett J, Ingbar D, Phan S, Bitterman PB, Henke CA
JournalAm J Pathol
Volume184
Issue5
Pagination1369-83
Date Published2014 May
ISSN1525-2191
KeywordsAnimals, Cell Line, Cell Separation, Fibroblasts, Gene Expression Profiling, Gene Expression Regulation, Heterografts, Humans, Idiopathic Pulmonary Fibrosis, Mesenchymal Stem Cells, Mice, Phenotype, Signal Transduction, Zebrafish
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.

DOI10.1016/j.ajpath.2014.01.012
Alternate JournalAm J Pathol
PubMed ID24631025
Grant ListP30 CA77598 / CA / NCI NIH HHS / United States
P01 HL91775 / HL / NHLBI NIH HHS / United States
8UL1TR000114-02 / TR / NCATS NIH HHS / United States
Related Faculty: 
Jose Jessurun, M.D.

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