title: Pulmonary vascular disease in mice xenografted with human BM progenitors from patients with pulmonary arterial hypertension.
abstract: Hematopoietic myeloid progenitors released into the circulation are able to promote vascular remodeling through endothelium activation and injury. Endothelial injury is central to the development of pulmonary arterial hypertension (PAH), a proliferative vasculopathy of the pulmonary circulation, but the origin of vascular injury is unknown. In the present study, mice transplanted with BM-derived CD133(+) progenitor cells from patients with PAH, but not from healthy controls, exhibited morbidity and/or death due to features of PAH: in situ thrombi and endothelial injury, angioproliferative remodeling, and right ventricular hypertrophy and failure. Myeloid progenitors from patients with heritable and/or idiopathic PAH all produced disease in xenografted mice. Analyses of hematopoietic transcription factors and colony formation revealed underlying abnormalities of progenitors that skewed differentiation toward the myeloid-erythroid lineage. The results of the present study suggest a causal role for hematopoietic stem cell abnormalities in vascular injury, right ventricular hypertrophy, and morbidity associated with PAH.
authors: Pathobiology, Lerner Research Institute and Respiratory Institute, Cleveland Clinic, Cleveland, OH 44195, USA. asosink@ccf.org
authors: Kewal
authors: K
authors: Asosingh
authors: Samar
authors: S
authors: Farha
authors: Alan
authors: A
authors: Lichtin
authors: Brian
authors: B
authors: Graham
authors: Deepa
authors: D
authors: George
authors: Micheala
authors: M
authors: Aldred
authors: Stanley L
authors: SL
authors: Hazen
authors: James
authors: J
authors: Loyd
authors: Rubin
authors: R
authors: Tuder
authors: Serpil C
authors: SC
authors: Erzurum
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000473:pathology; D016026:Bone Marrow Transplantation / Q000009:adverse effects* / Q000379:methods; D002478:Cells, Cultured; D065627:Familial Primary Pulmonary Hypertension; D005260:Female; D006801:Humans; D006976:Hypertension, Pulmonary / Q000473:pathology*; D008171:Lung Diseases / Q000209:etiology*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D011651:Pulmonary Artery / Q000473:pathology; D033581:Stem Cell Transplantation / Q000009:adverse effects* / Q000379:methods; D014183:Transplantation, Heterologous / Q000009:adverse effects; D014652:Vascular Diseases / Q000209:etiology*