title: Lung bone marrow-derived hematopoietic progenitor cells enhance pulmonary fibrosis.
abstract: BACKGROUND
  Bone marrow (BM)-derived cells have been implicated in pulmonary fibrosis. However, their precise role in pathogenesis is incompletely understood.
  
  
  OBJECTIVE
  To elucidate roles of BM-derived cells in bleomycin-induced pulmonary fibrosis, and clarify their potential relationship to lung hematopoietic progenitor cells (LHPCs).
  
  
  METHODS
  GFP BM-chimera mice treated with or without bleomycin were used to assess the BM-derived cells.
  
  
  RESULTS
  GFP(+) cells in the chimera lung were found to be comprised of two distinct phenotypes: GFP(hi) and GFP(low) cells. The GFP(hi), but not GFP(low), population was significantly increased after bleomycin treatment. Flow-cytometric analysis and quantitative real-time polymerase chain reaction revealed that GFP(hi) cells exhibited phenotypic characteristics of CD11c(+) dendritic cells and macrophages. GFP(hi) cell conditioned media were chemotactic for fibroblasts obtained from fibrotic but not normal lung in vitro. Moreover, adoptive transfer of GFP(hi) cells exacerbated fibrosis in recipient mice, similar to that seen on adoptive transfer of BM-derived CD11c(+) cells from donor bleomycin-treated mice. Next, we evaluated the potential of LHPCs as the source of GFP(hi) cells. Isolation of LHPCs by flow sorting revealed enrichment in cKit(+)/Sca1(-)/Lin(-) cells, most of which were GFP(+) indicating their BM origin. The number of LHPCs increased rapidly after bleomycin treatment. Furthermore, stem cell factor induced LHPC proliferation, whereas granulocyte-macrophage-colony stimulating factor induced differentiation to GFP(hi) cells.
  
  
  CONCLUSIONS
  BM-derived LHPCs with a novel phenotype could differentiate into GFP(hi) cells, which enhanced pulmonary fibrosis. Targeting this mobilized LHPCs might represent a novel therapeutic approach in chronic fibrotic lung diseases.
authors.affiliation: 1 Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan; and.
authors.forename: Taku
authors.initials: T
authors.lastname: Nakashima
authors.forename: Tianju
authors.initials: T
authors.lastname: Liu
authors.forename: Hongfeng
authors.initials: H
authors.lastname: Yu
authors.forename: Lin
authors.initials: L
authors.lastname: Ding
authors.forename: Matthew
authors.initials: M
authors.lastname: Ullenbruch
authors.forename: Biao
authors.initials: B
authors.lastname: Hu
authors.forename: Zhe
authors.initials: Z
authors.lastname: Wu
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Oguro
authors.forename: Sem H
authors.initials: SH
authors.lastname: Phan
mesh_terms: D000818:Animals; D001761:Bleomycin / Q000494:pharmacology; D002478:Cells, Cultured; D002678:Chimera / Q000502:physiology; D004195:Disease Models, Animal; D005260:Female; D006412:Hematopoietic Stem Cells / Q000502:physiology*; D008168:Lung / Q000166:cytology / Q000187:drug effects / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000209:etiology* / Q000473:pathology
chemical_list: D001761:Bleomycin