title: Innate immunity in the therapeutic actions of endothelial progenitor cells in pulmonary hypertension.
abstract: Direct injection of endothelial progenitor cells (EPCs) into the circulation has shown therapeutic benefit in both experimental models and clinical studies of pulmonary arterial hypertension (PAH). Using the monocrotaline (MCT)-induced rat model of PAH, we investigated the role of innate immunity in the therapeutic activity of two types of putative EPCs derived from human peripheral blood mononuclear cells: an early population of endothelial-like, culture-modified monocytes (E-CMMs) and late-outgrowth EPCs (L-EPCs), which exhibit a strong endothelial phenotype. In the athymic nude rat, E-CMMs prevented MCT-induced increases in right ventricular systolic pressure (P < 0.001) and right ventricular hypertrophy (P < 0.01) when administered 3 days after MCT challenge, whereas L-EPCs were ineffective. However, in both cases, there was a lack of cell persistence within the lungs at 24 hours after injection, likely due to residual natural killer (NK) cell activity in the model. Although ablation of NK and NK-T cells with anti-asialo-GM-1 antiserum enhanced the retention of both E-CMMs and L-EPCs, still no benefit was seen with L-EPCs, and the efficacy of E-CMMs was lost. In vitro characterization revealed that E-CMMs resemble a regulatory subtype of dendritic cells, producing IL-10, but not IL-12, in response to inflammatory stimuli. Coculture studies demonstrated the capacity of E-EPCs to stimulate autologous human and nude rat NK cells in vitro. These data support a novel mode of action for human E-CMMs in the prevention of PAH, whereby they act through an immune-dependent mechanism, potentially involving the stimulation of NK cells.
authors.affiliation: Ottawa Hospital Research Institute and the University of Ottawa, Ottawa, Ontario, K1H 8L6 Canada.
authors.forename: Mark L
authors.initials: ML
authors.lastname: Ormiston
authors.forename: Yupu
authors.initials: Y
authors.lastname: Deng
authors.forename: Duncan J
authors.initials: DJ
authors.lastname: Stewart
authors.forename: David W
authors.initials: DW
authors.lastname: Courtman
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D001794:Blood Pressure; D016923:Cell Death; D002478:Cells, Cultured; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000166:cytology* / Q000276:immunology*; D005434:Flow Cytometry; D006801:Humans; D006976:Hypertension, Pulmonary / Q000276:immunology* / Q000503:physiopathology / Q000628:therapy*; D007113:Immunity, Innate / Q000276:immunology*; D007694:Killer Cells, Natural / Q000166:cytology / Q000276:immunology; D008168:Lung / Q000276:immunology / Q000473:pathology / Q000503:physiopathology; D016686:Monocrotaline; D009000:Monocytes / Q000166:cytology / Q000276:immunology; D051381:Rats; D011923:Rats, Nude; D013154:Spleen / Q000166:cytology; D013234:Stem Cells / Q000166:cytology* / Q000276:immunology*
chemical_list: D015415:Biomarkers; D016686:Monocrotaline