title: C-kit-positive cells accumulate in remodeled vessels of idiopathic pulmonary arterial hypertension.
abstract: BACKGROUND
  C-kit(+) cells, including bone marrow (BM)-derived progenitors and mast cells, may participate in vascular remodelling. Because recent studies suggest that c-kit may be a target for innovative therapies in experimental pulmonary hypertension, we investigated the contribution of c-kit(+) cells in human idiopathic pulmonary arterial hypertension (IPAH).
  
  
  OBJECTIVE
  To investigate the contribution of c-kit(+) cells in human IPAH.
  
  
  METHODS
  Single c-kit, CXCL12/SDF-1α, CXCR4, CD34, and multiple c-kit, α-smooth muscle actin (α-SMA) and tryptase immunostainings were performed in IPAH lungs. C-kit mRNA expression was quantified by real-time polymerase chain reaction in microdissected pulmonary arteries from patients with IPAH and control subjects. Phenotype and function of circulating progenitors were analyzed by flow cytometry. Plasma levels of soluble c-kit and CXCL12/SDF-1α were measured by ELISA.
  
  
  RESULTS
  Infiltration of c-kit(+) cells in pulmonary arterial lesions was associated with an increase in c-kit mRNA expression (P < 0.01 compared with control subjects). Both c-kit(+)/tryptase(+) mast cells and c-kit(+)/tryptase(-) BM-derived cells were increased in pulmonary arteries of patients with IPAH compared with control subjects (106.6 ± 54.5 vs. 28 ± 16.8/mm(2) and 143.8 ± 101.1 vs. 23.3 ± 11.9/mm(2); all P<0.01). Plasma-soluble c-kit was increased in IPAH compared with control subjects (27.4 ± 12.4 vs. 19.5 ± 5.8 ng/ml; P<0.05). Two populations of circulating BM-derived cells (lin-CD34(high)CD133(high) [c-kit(high)CXCR4(low)] and lin-CD34(low)CD133(-) [c-kit(low)CXCR4(high)]) were increased in IPAH compared with control subjects (P=0.01). Pulmonary arterial lesions were associated with vasa vasorum expansion expressing CXL12/SDF-1α that may recruit c-kit(+) cells.
  
  
  CONCLUSIONS
  In IPAH, c-kit(+) cells infiltrate pulmonary arterial lesions and may participate to vascular remodeling. Therefore, c-kit may represent a potential target for innovative PAH therapy.
authors.affiliation: University Paris-Sud, Faculté de Médecine, Kremlin-Bicêtre, France.
authors.forename: David
authors.initials: D
authors.lastname: Montani
authors.forename: Frédéric
authors.initials: F
authors.lastname: Perros
authors.forename: Natalia
authors.initials: N
authors.lastname: Gambaryan
authors.forename: Barbara
authors.initials: B
authors.lastname: Girerd
authors.forename: Peter
authors.initials: P
authors.lastname: Dorfmuller
authors.forename: Laura C
authors.initials: LC
authors.lastname: Price
authors.forename: Alice
authors.initials: A
authors.lastname: Huertas
authors.forename: Hamida
authors.initials: H
authors.lastname: Hammad
authors.forename: Bart
authors.initials: B
authors.lastname: Lambrecht
authors.forename: Gérald
authors.initials: G
authors.lastname: Simonneau
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Launay
authors.forename: Sylvia
authors.initials: S
authors.lastname: Cohen-Kaminsky
authors.forename: Marc
authors.initials: M
authors.lastname: Humbert
mesh_terms: D018952:Antigens, CD34 / Q000378:metabolism; D054377:Chemokine CXCL12 / Q000378:metabolism; D003238:Connective Tissue / Q000378:metabolism; D005434:Flow Cytometry; D006801:Humans; D006976:Hypertension, Pulmonary / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D007150:Immunohistochemistry; D008407:Mast Cells / Q000378:metabolism / Q000473:pathology; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism*; D011651:Pulmonary Artery / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D019718:Receptors, CXCR4 / Q000378:metabolism; D013234:Stem Cells / Q000378:metabolism* / Q000473:pathology; D053802:Tryptases / Q000378:metabolism; D014651:Vasa Vasorum / Q000378:metabolism
chemical_list: D018952:Antigens, CD34; C527276:CXCR4 protein, human; D054377:Chemokine CXCL12; D019718:Receptors, CXCR4; D019009:Proto-Oncogene Proteins c-kit; D053802:Tryptases