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. 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. Progressive scarring of the heart, blood vessels, lung, liver, kidney, and brain is a leading cause of death worldwide.1Wynn T.A. Ramalingam T.R. Mechanisms of fibrosis: therapeutic translation for fibrotic disease.Nat Med. 2012; 18: 1028-1040Crossref PubMed Scopus (2163) Google Scholar Characteristic of these diseases, idiopathic pulmonary fibrosis (IPF) is a prevalent and progressive process.2Fernandez I.E. Eickelberg O. New cellular and molecular mechanisms of lung injury and fibrosis in idiopathic pulmonary fibrosis.Lancet. 2012; 380: 680-688Abstract Full Text Full Text PDF PubMed Scopus (314) Google Scholar, 3King Jr., T.E. Pardo A. Selman M. Idiopathic pulmonary fibrosis.Lancet. 2011; 378: 1949-1961Abstract Full Text Full Text PDF PubMed Scopus (1376) Google Scholar, 4Noble P.W. Idiopathic pulmonary fibrosis: natural history and prognosis.Clin Chest Med. 2006; 27 (v): S11-S16Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar, 5Noble P.W. Barkauskas C.E. Jiang D. Pulmonary fibrosis: patterns and perpetrators.J Clin Invest. 2012; 122: 2756-2762Crossref PubMed Scopus (353) Google Scholar, 6Raghu G. Weycker D. Edelsberg J. Bradford W.Z. Oster G. Incidence and prevalence of idiopathic pulmonary fibrosis.Am J Respir Crit Care Med. 2006; 174: 810-816Crossref PubMed Scopus (1008) Google Scholar In IPF, the fibroblast population expands within alveolar structures, resulting in scarred nonfunctional airspaces, progressive hypoxemia, and death by asphyxiation. As the disease process evolves, fibrosis spreads contiguously from affected alveoli into anatomically intact adjacent gas exchange units, resulting in an expanding reticular network of fibrotic tissue.7King T.E. Costabel U. Cordier J.F. DoPico G.A. DuBois R.M. Lynch D. Lynch III J.P. Myers J. Panos R. Raghu G. Schwartz D. Smith C.M. American Thoracic Society. Idiopathic pulmonary fibrosis: diagnosis and treatment. International consensus statement. American Thoracic Society (ATS), and the European Respiratory Society (ERS).Am J Respir Crit Care Med. 2000; 161: 646-664Crossref PubMed Scopus (997) Google Scholar, 8Travis W.D. King T.E. Bateman E.D. Lynch D.A. Capron F. Center D. Colby T.V. Cordier J.F. DuBois R.M. Galvin J. Grenier P. Hansell D.M. Hunninghake G.W. Kitaichi M. Muller N.L. Myers J.L. Nagai S. Nicholson A. Raghu G. Wallaert B. American Thoracic SocietyEuropean Respiratory SocietyAmerican Thoracic Society/European Respiratory Society International Multidisciplinary of the Idiopathic of the American Thoracic Society (ATS), and the European Respiratory Society by the of and by the J Respir Crit Care Med. PubMed Scopus Google Scholar, are of lung injury the fibroblast J Respir Crit Care Med. 2006; 174: PubMed Scopus Google Scholar, The of the in idiopathic pulmonary fibrosis. and of of J Google Scholar, P.W. Idiopathic pulmonary fibrosis: into Chest Med. Full Text Full Text PDF PubMed Scopus Google Scholar, M. King T.E. Pardo A. American Thoracic SocietyEuropean Respiratory SocietyAmerican of Chest pulmonary fibrosis: and and for Med. PubMed Scopus Google Scholar IPF lung fibroblasts that them from normal lung fibroblasts. signaling in the IPF fibroblast leads to of and signaling D. R. D. J. J. S. M. J. P. signaling of lung fibroblasts from patients with idiopathic pulmonary Med. PubMed Scopus Google Scholar, J. J. J. of in idiopathic pulmonary fibrosis.Am J Full Text Full Text PDF PubMed Scopus Google Scholar, J. J. P. J. Smith R. J. P. the of fibroblasts from patients with idiopathic pulmonary fibrosis by of the J 2012; Full Text Full Text PDF PubMed Scopus Google into model IPF fibroblasts form fibrotic P. J. M. novel zebrafish model to fibroblast in and 2012; PubMed Scopus Google Scholar, C.M. of pulmonary fibrosis by the of pulmonary fibroblasts to J Full Text Full Text PDF PubMed Scopus Google Scholar Despite their in progressive fibrotic of the lung, the of the IPF fibroblast are is a for and progenitor cells a of the population in and lung tissue and progenitor cells that and to cells that in the and and in to A. a population that to the J 161: Full Text Full Text PDF PubMed Scopus Google Scholar, J. M. D. F. B. J. A. P. G. S. F. R. A. J. P. for lung J Med. 2011; PubMed Scopus Google Scholar, S. S. D. of cells in normal lung and lung Full Text Full Text PDF PubMed Scopus Google Scholar, M. of novel pulmonary form and of the lung PubMed Scopus Google Scholar, F. D. M. in lung is in to and fibrotic A. PubMed Scopus Google Scholar, cells in lung and the for therapeutic and J Respir 2006; PubMed Scopus Google Scholar, R. D. J. A. of an mouse lung mesenchymal progenitor J Respir PubMed Scopus Google Scholar, R. S. A. lung population cells are and J Respir PubMed Scopus Google Scholar, A. cells and therapies in lung and lung PubMed Scopus Google Scholar tissue pathological progenitors that and to produce daughter M. A. identification of A. PubMed Scopus Google Scholar, D. is a that from a Med. PubMed Scopus Google Scholar, The and Med. 2011; PubMed Scopus Google Scholar, A. M. F. M. J. The cells with properties of Full Text Full Text PDF PubMed Scopus Google Scholar, and PubMed Scopus Google Scholar, S. P. is from mesenchymal progenitor PubMed Scopus Google progenitor cells have in lung S. A. A. cells in of J Respir Crit Care Med. 2011; PubMed Scopus Google Scholar, Smith A. S. M. for mesenchymal cells in lung from of Clin Invest. PubMed Scopus Google Scholar Here, we report the identification of a of cells in the lungs of patients with IPF with the properties of mesenchymal progenitors. expression of IPF lung mesenchymal progenitors them from mesenchymal progenitors isolated in a from the lungs of with of with The cellular progeny of IPF mesenchymal progenitors of the of the IPF including increased of increased expression of α-smooth muscle actin and and the ability to form fibrotic lesions in model organisms. of IPF lung revealed mesenchymal progenitor cells and cells of their progeny the fibrotic reticulum. is the report in progressive fibrotic that tissue mesenchymal progenitor cells that are cells of origin for fibrosis-mediating fibroblasts. a of from the of and in with the of Care and lung mesenchymal from patients for IPF, including a pathological diagnosis of W.D. King T.E. Bateman E.D. Lynch D.A. Capron F. Center D. Colby T.V. Cordier J.F. DuBois R.M. Galvin J. Grenier P. Hansell D.M. Hunninghake G.W. Kitaichi M. Muller N.L. Myers J.L. Nagai S. Nicholson A. Raghu G. Wallaert B. American Thoracic SocietyEuropean Respiratory SocietyAmerican Thoracic Society/European Respiratory Society International Multidisciplinary of the Idiopathic of the American Thoracic Society (ATS), and the European Respiratory Society by the of and by the J Respir Crit Care Med. PubMed Scopus Google Scholar to in to patients with IPF with nonfibrotic lung the of these we nonfibrotic fibroblast from lung tissue by the disease from lungs, mesenchymal and B. J. B. R. J. M. P. cells isolated lung injury an Clin Invest. PubMed Scopus Google Scholar, O. D. D. 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J. of in idiopathic pulmonary fibrosis.Am J Full Text Full Text PDF PubMed Scopus Google Scholar, J. J. P. J. Smith R. J. P. the of fibroblasts from patients with idiopathic pulmonary fibrosis by of the J 2012; Full Text Full Text PDF PubMed Scopus Google Scholar IPF and progeny daughter from cells that IPF and progenitors isolated from IPF and mesenchymal by that for progenitors into of tissue and to and for The population IPF cells by that from a IPF and mesenchymal a of one into with that a of The IPF and to tissue and to and for IPF and lung tissue and The in a with in and in a for in for in normal to of and by for with an and to in the and α-smooth muscle actin with in for by for by a we the in a with the to normal normal in a for the and the with for and to for with a and with a into the of the zebrafish the P. J. 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D. for mesenchymal The International Society for 2006; Full Text Full Text PDF PubMed Scopus Google Scholar, T.A. of to the alveolar fibrotic J Full Text Full Text PDF PubMed Scopus Google Scholar to and IPF cells and expression of the and and for the and of is the ability of a a to B. A. Full Text Full Text PDF PubMed Scopus Google Scholar IPF and cells In with IPF and cells mesenchymal the progenitor and and that mesenchymal from IPF and lungs contain mesenchymal progenitor cells that properties with molecular that and IPF mesenchymal progenitor we in gene expression IPF and mesenchymal progenitor cells the of of with of the revealed a distinct IPF molecular in we a gene gene for PubMed Scopus Google Scholar, A. J. M. S. S. S. J. M. M. R. G. J. in Google Scholar IPF mesenchymal progenitor cells from in with a of gene to of gene expression and the of transcriptional we that IPF and mesenchymal progenitor cells and and expression in IPF mesenchymal and and expression in mesenchymal the transcriptional for of with IPF mesenchymal progenitors a of gene expression that them from their IPF lung fibroblasts have phenotypic that them from D. R. D. J. J. S. M. J. P. signaling of lung fibroblasts from patients with idiopathic pulmonary Med. PubMed Scopus Google Scholar, J. J. J. of in idiopathic pulmonary fibrosis.Am J Full Text Full Text PDF PubMed Scopus Google Scholar, J. J. P. J. Smith R. J. P. the of fibroblasts from patients with idiopathic pulmonary fibrosis by of the J 2012; Full Text Full Text PDF PubMed Scopus Google Scholar, M. J. Selman M. Pardo A. from idiopathic pulmonary fibrosis and normal lungs in and tissue of J Respir PubMed Scopus Google Scholar of and of and and and pathological of the signaling resulting in of the daughter cells of mesenchymal progenitors for these hallmarks, we to cells from IPF and mesenchymal and them to and that mesenchymal progenitors and in fibroblast and expression of and from the to the for a of F. R. F. M. D. G. F. cells in 2012; PubMed Scopus Google Scholar In with of the progeny of mesenchymal progenitors fibroblast and expression in and from the to the in IPF progeny and the of in the daughter cells of IPF mesenchymal progenitors IPF fibroblast increased of and and of and and These data IPF mesenchymal progenitors produce daughter cells with the of IPF fibroblasts. into zebrafish embryos IPF fibroblasts form fibrotic P. J. 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Barkauskas C.E. Jiang D. Pulmonary fibrosis: patterns and perpetrators.J Clin Invest. 2012; 122: 2756-2762Crossref PubMed Scopus (353) Google Scholar Here, we report the of mesenchymal progenitor cells from the IPF lung that fibroblasts the IPF that IPF mesenchymal progenitor cells are in the IPF fibrotic isolated and from IPF lungs, and that the daughter cells of these IPF mesenchymal progenitors fibrotic lesions into model organisms. 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Despite of the origin of the fibroblasts that fibrotic that to the origin of fibroblasts injury in model have progenitor cells in pulmonary Clin Invest. PubMed Scopus Google Scholar, A. T.E. the and origin of in fibrosis.Am J Full Text Full Text PDF PubMed Scopus Google Scholar, D. mesenchymal in pulmonary fibrosis and is by the A. 2006; PubMed Scopus Google Scholar, A. G. D. J. J. R.M. M. are an of in idiopathic pulmonary fibrosis.Am J Respir Crit Care Med. PubMed Scopus Google Scholar, Barkauskas C.E. J. P.W. to pulmonary fibrosis for to mesenchymal A. 2011; PubMed Scopus Google Scholar in a mouse model is that to lung Barkauskas C.E. J. P.W. to pulmonary fibrosis for to mesenchymal A. 2011; PubMed Scopus Google Scholar in the of fibrosis. Here, we report the and molecular of mesenchymal progenitor from a fibrotic that are of daughter cells that have an activated and form a fibrotic in by for a therapeutic that target fibrogenic mesenchymal progenitor cells fibrogenic fibroblasts that of for and and for of for the of the a by the and of the The and for with of mesenchymal mesenchymal progenitors and their daughter are contrast of mesenchymal cells from lungs, mesenchymal progenitor cells isolated by and the progeny of the mesenchymal progenitors. with of mesenchymal progenitor cells in zebrafish IPF mesenchymal progenitor cells that with and into zebrafish embryos the normal mesenchymal cells with and into zebrafish embryos is a progenitor cells to the and in normal are and of embryos to the with the IPF to the heart, and to IPF mesenchymal progenitor cells in the and to the is a of the from a with with zebrafish cells and is for cells into P. J. M. novel zebrafish model to fibroblast in and 2012; PubMed Scopus Google Scholar The data the ability of mesenchymal progenitor cells to with cells in contrast of the of the the within the of within the with progeny of IPF mesenchymal progenitor cells form an fibrotic and in IPF mesenchymal progenitor progeny with and into zebrafish IPF progeny an fibrotic reticular cells an is of the IPF and progeny the of an fibrotic by the IPF are of from embryos with IPF with are The fibrotic is by a is in IPF mesenchymal progenitor are of from and IPF embryos that with a and and with embryos with a IPF lung tissue cells in a a for the cells in the IPF embryos and fibrotic tissue in in zebrafish with mesenchymal progenitor progeny form fibrotic lesions in the lungs of The progeny of mesenchymal progenitor cells into analysis with an to cells within the mouse The lungs anatomically with of mesenchymal progenitor cells that for cells that with into tissue and in cells from the and for and the of the cells for and for and for is the population of a of The for the population is to a with progeny of a mesenchymal progenitor the fibroblast cells that in with and for IPF and progenitor cells and for from and for in and of IPF and progeny is are of the progeny from a IPF and mesenchymal progenitor for collagen and and and and IPF and and a are the for the IPF and mesenchymal from the progenitors fibroblasts and IPF fibroblasts progeny with and into zebrafish is an of zebrafish embryos with by the progeny of a cells a in with the middle with and to the α-smooth muscle with analysis of IPF lung IPF lung tissue with with analysis of IPF lung tissue for of and of of IPF lung tissue patients with for and is in and in IPF and lung tissue with and and with analysis of IPF lung tissue for IPF cells with a and IPF lung tissue with normal IPF lung tissue adjacent to a fibrotic with analysis of lung of alveolar within lung tissue with to and of cells are in anatomically alveolar in lung in a in in a cells in a with of gene expression data from the progeny of mesenchymal progenitor are expression of by represent the of and are in with with with in American of that are in the of The American of PDF