title: Bone Marrow-derived Cells Contribute to the Pathogenesis of Pulmonary Arterial Hypertension.
abstract: BACKGROUND
  Pulmonary arterial hypertension (PAH) is a progressive lung disease of the pulmonary microvasculature. Studies suggest that bone marrow (BM)-derived circulating cells may play an important role in its pathogenesis.
  
  
  OBJECTIVE
  We used a genetic model of PAH, the Bmpr2 mutant mouse, to study the role of BM-derived circulating cells in its pathogenesis.
  
  
  METHODS
  Recipient mice, either Bmpr2(R899X) mutant or controls, were lethally irradiated and transplanted with either control or Bmpr2(R899X) BM cells. Donor cells were traced in female recipient mice by Y chromosome painting. Molecular and function insights were provided by expression and cytokine arrays combined with flow cytometry, colony-forming assays, and competitive transplant assays.
  
  
  RESULTS
  We found that mutant BM cells caused PAH with remodeling and inflammation when transplanted into control mice, whereas control BM cells had a protective effect against the development of disease, when transplanted into mutant mice. Donor BM-derived cells were present in the lungs of recipient mice. Functional and molecular analysis identified mutant BM cell dysfunction suggestive of a PAH phenotype soon after activation of the transgene and long before the development of lung pathology.
  
  
  CONCLUSIONS
  Our data show that BM cells played a key role in PAH pathogenesis and that the transplanted BM cells were able to drive the lung phenotype in a myeloablative transplant model. Furthermore, the specific cell types involved were derived from hematopoietic stem cells and exhibit dysfunction long before the development of lung pathology.
authors.affiliation: 1 Division of Medical Genetics and Genomic Medicine, Department of Pediatrics.
authors.forename: Ling
authors.initials: L
authors.lastname: Yan
authors.affiliation: 2 Division of Respiratory and Critical Care, Department of Medicine.
authors.forename: Xinping
authors.initials: X
authors.lastname: Chen
authors.affiliation: 2 Division of Respiratory and Critical Care, Department of Medicine.
authors.forename: Megha
authors.initials: M
authors.lastname: Talati
authors.affiliation: 1 Division of Medical Genetics and Genomic Medicine, Department of Pediatrics.
authors.forename: Bethany Womack
authors.initials: BW
authors.lastname: Nunley
authors.affiliation: 2 Division of Respiratory and Critical Care, Department of Medicine.
authors.forename: Santhi
authors.initials: S
authors.lastname: Gladson
authors.affiliation: 2 Division of Respiratory and Critical Care, Department of Medicine.
authors.forename: Tom
authors.initials: T
authors.lastname: Blackwell
authors.affiliation: 1 Division of Medical Genetics and Genomic Medicine, Department of Pediatrics.
authors.forename: Joy
authors.initials: J
authors.lastname: Cogan
authors.affiliation: 3 Division of Allergy, Immunology and Pulmonary Medicine, Department of Pediatrics, and.
authors.forename: Eric
authors.initials: E
authors.lastname: Austin
authors.affiliation: 4 Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee.
authors.forename: Ferrin
authors.initials: F
authors.lastname: Wheeler
authors.affiliation: 2 Division of Respiratory and Critical Care, Department of Medicine.
authors.forename: James
authors.initials: J
authors.lastname: Loyd
authors.affiliation: 2 Division of Respiratory and Critical Care, Department of Medicine.
authors.forename: James
authors.initials: J
authors.lastname: West
authors.affiliation: 1 Division of Medical Genetics and Genomic Medicine, Department of Pediatrics.
authors.forename: Rizwan
authors.initials: R
authors.lastname: Hamid
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation; D004195:Disease Models, Animal; D005260:Female; D005434:Flow Cytometry; D006412:Hematopoietic Stem Cells / Q000473:pathology*; D006976:Hypertension, Pulmonary / Q000473:pathology*; D008168:Lung / Q000473:pathology*; D051379:Mice
keywords: Bmpr2; bone marrow cells; hematopoietic stem cells; pulmonary arterial hypertension; transplantation