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

  • Xia, Hong
  • Bodem, Vidya
  • Benyumov, Alexey
  • Hergert, Polla
  • Tank, Damien
  • Herrera, Jeremy
  • Braziunas, Jeff
  • Larsson, Ola
  • Parker, Matthew
  • Rossi, Daniel
  • Smith, Karen
  • Peterson, Mark
  • Limper, Andrew
  • Jessurun, Jose
  • Connett, John
  • Ingbar, David
  • Phan, Sem
  • Bitterman, Peter B.
  • Henke, Craig A.1, 2, 3, 2, 4, 2, 5, 2, 6, 7, 1, 8, 9, 10
  • 1 Department of Medicine
  • 2 University of Minnesota
  • 3 Department of Pharmacology
  • 4 Department of Laboratory Medicine and Pathology
  • 5 Division of Biostatistics School of Public Health
  • 6 Department of Oncology and Pathology
  • 7 Karolinska Institute
  • 8 Mayo Clinic College of Medicine
  • 9 Department of Pathology
  • 10 University of Michigan Medical School
Published Article
The American Journal of Pathology
Elsevier BV
Publication Date
Jan 01, 2014
Accepted Date
Jan 02, 2014
DOI: 10.1016/j.ajpath.2014.01.012


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.

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