Abstract 2365: Multipotent Mesenchymal Stem Cells Contribute to Vascular Remodeling in Patients With Chronic Thromboembolic Pulmonary Hypertension
Despite knowledge of the clinical characteristics of chronic thromboembolic pulmonary hypertension (CTEPH), the cellular and molecular determinants of the disease remain poorly understood. It has been postulated that proliferation of adventitial fibroblasts, circulating progenitor cells and myofibroblasts contributes to pulmonary vascular wall thickening. This study aimed to identify the cells contributing to the remodeling/hypertrophy, and to elucidate potential mechanisms involved in the development of vascular remodeling in CTEPH patients. Histology of endarterectomized CTEPH tissues identified significant neointimal formation. Isolated cells from these tissues had diverse morphological heterogeneity and grew in a honeycomb-like network indicative of fibroblast-like cells. Additionally, cells frequently formed colonies of small spherical cells fanned by elongated cells reminiscent of more primitive fibroblast-colony forming units. The co-expression of intermediate filament vimentin and smooth muscle α-actin indicates the presence of myofibroblasts. Expression of cell surface markers typical of mesenchymal progenitor cells was investigated using immunocytochemistry and flow cytometry; cells were >99% CD44+, CD73+, CD90+, CD166+, >60% CD29+, 45–99% CD105+ and negative for CD34 and CD45. In addition to myogenesis, cells isolated from endarterectomized tissues from CTEPH patients were capable of undergoing adipogenic differentiation, determined by Oil Red O staining and osteogenic differentiation, determined by alkaline phosphatase and Alizarin Red staining. Additionally, a population of Stro-1+ cells (~4.2%), a marker of bone marrow-derived stromal cells, was sorted by flow cytometry and also capable of adipogenesis and osteogenesis. This study is the first to investigate the cellular phenotypes and identify myofibroblasts and multipotent mesenchymal progenitor cells as the predominant cells comprising the endarterectomized tissues from patients with CTEPH. These findings will be critical in establishing future studies to determine the cellular and molecular mechanisms of the disease and in the development of novel and much needed therapeutic approaches.