TY - JOUR
T1 - Identification of a cell-of-origin for fibroblasts comprising the fibrotic reticulum in idiopathic pulmonary fibrosis
AU - Xia, Hong
AU - Bodempudi, Vidya
AU - Benyumov, Alexey
AU - Hergert, Polla
AU - Tank, Damien
AU - Herrera, Jeremy
AU - Braziunas, Jeff
AU - Larsson, Ola
AU - Parker, Matthew
AU - Rossi, Daniel
AU - Smith, Karen
AU - Peterson, Mark
AU - Limper, Andrew
AU - Jessurun, Jose
AU - Connett, John
AU - Ingbar, David
AU - Phan, Sem
AU - Bitterman, Peter B.
AU - Henke, Craig A.
N1 - Funding Information:
Supported by National Heart, Lung, and Blood Institute grants R01 HL074882 and P01 HL91775 (C.A.H.) and R01 HL089249 (P.B.B.); funds provided by the O’Brien family ; the Swedish Research Council (O.L.); the National Center for Advancing Translational Sciences of the National Institutes of Health award 8UL1TR000114-02 ; and the Flow Cytometry Core Facility of the Masonic Cancer Center , a comprehensive cancer center designated by the National Cancer Institute, supported in part by P30 CA77598 and the University of Minnesota Imaging Center .
PY - 2014/5
Y1 - 2014/5
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84899547894&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84899547894&partnerID=8YFLogxK
U2 - 10.1016/j.ajpath.2014.01.012
DO - 10.1016/j.ajpath.2014.01.012
M3 - Article
C2 - 24631025
AN - SCOPUS:84899547894
SN - 0002-9440
VL - 184
SP - 1369
EP - 1383
JO - American Journal of Pathology
JF - American Journal of Pathology
IS - 5
ER -