title: 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.
authors.affiliation: Department of Medicine, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Hong
authors.initials: H
authors.lastname: Xia
authors.affiliation: Department of Medicine, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Vidya
authors.initials: V
authors.lastname: Bodempudi
authors.affiliation: Department of Medicine, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Alexey
authors.initials: A
authors.lastname: Benyumov
authors.affiliation: Department of Medicine, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Polla
authors.initials: P
authors.lastname: Hergert
authors.affiliation: Department of Medicine, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Damien
authors.initials: D
authors.lastname: Tank
authors.affiliation: Department of Medicine, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Herrera
authors.affiliation: Department of Pharmacology, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Jeff
authors.initials: J
authors.lastname: Braziunas
authors.affiliation: Department of Oncology and Pathology, Karolinska Institute, Stockholm, Sweden.
authors.forename: Ola
authors.initials: O
authors.lastname: Larsson
authors.affiliation: Department of Medicine, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Matthew
authors.initials: M
authors.lastname: Parker
authors.affiliation: Department of Medicine, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Daniel
authors.initials: D
authors.lastname: Rossi
authors.affiliation: Department of Medicine, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Karen
authors.initials: K
authors.lastname: Smith
authors.affiliation: Department of Medicine, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Mark
authors.initials: M
authors.lastname: Peterson
authors.affiliation: Department of Medicine, Mayo Clinic College of Medicine, Rochester, Minnesota.
authors.forename: Andrew
authors.initials: A
authors.lastname: Limper
authors.affiliation: Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Jose
authors.initials: J
authors.lastname: Jessurun
authors.affiliation: Division of Biostatistics School of Public Health, University of Minnesota, Minneapolis, Minnesota.
authors.forename: John
authors.initials: J
authors.lastname: Connett
authors.affiliation: Department of Medicine, University of Minnesota, Minneapolis, Minnesota.
authors.forename: David
authors.initials: D
authors.lastname: Ingbar
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan.
authors.forename: Sem
authors.initials: S
authors.lastname: Phan
authors.affiliation: Department of Medicine, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Peter B
authors.initials: PB
authors.lastname: Bitterman
authors.affiliation: Department of Medicine, University of Minnesota, Minneapolis, Minnesota. Electronic address: henke002@umn.edu.
authors.forename: Craig A
authors.initials: CA
authors.lastname: Henke
mesh_terms: D000818:Animals; D002460:Cell Line; D002469:Cell Separation; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D064593:Heterografts; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis / Q000235:genetics / Q000473:pathology*; D059630:Mesenchymal Stem Cells / Q000473:pathology; D051379:Mice; D010641:Phenotype; D015398:Signal Transduction / Q000235:genetics; D015027:Zebrafish