Multipotent mesenchymal progenitor cells are present in endarterectomized tissues from patients with chronic thromboembolic pulmonary hypertension

Abstract

Factors contributing to the development of a fibrotic vascular scar and pulmonary vascular remodeling leading to chronic thromboembolic pulmonary hypertension (CTEPH) are still unknown. This study investigates the potential contribution of multipotent progenitor cells and myofibroblasts to the development and progression of CTEPH. Histological examination of endarterectomized tissues from patients with CTEPH identified significant neointimal formation. Morphological heterogeneity was observed in cells isolated from these tissues, including a network-like growth pattern and the formation of colony-forming unit-fibroblast-like colonies (CFU-F). Cells typically coexpressed intermediate filaments vimentin and smooth muscle alpha-actin. Cells were characterized by immunofluorescence and quantitated by fluorescent-activated cell sorting (FACS) for the presence of cell surface markers typical of mesenchymal progenitor cells; cells were >99% CD44(+) CD73(+), CD90(+), CD166(+); >80% CD29(+); 45-99% CD105(+); CD34(-) and CD45(-). Cells were capable of adipogenic and osteogenic differentiation, determined by Oil Red O and Alizarin Red staining, respectively. Additionally, a population of Stro-1(+) cells, a marker of bone marrow-derived stromal cells (4.2%), was sorted by FACS and also capable of adipogenic and osteogenic differentiation. In conclusion, this study is the first to identify a myofibroblast cell phenotype to be predominant within endarterectomized tissues, contributing extensively to the vascular lesion/clot. This cell may arise from transdifferentiation of adventitial fibroblasts or differentiation of mesenchymal progenitor cells. The unique microenvironment created by the stabilized clot is likely a factor in stimulating such cellular changes. These findings will be critical in establishing future studies in the development of novel and much needed therapeutic approaches for pulmonary hypertension.

Characterization of sarcoma-like cells derived from endarterectomized tissues from patients with CTEPH and establishment of a mouse model of pulmonary artery intimal sarcoma

“…Tumors were generated by subcutaneous injection of SCL and intravenous tail vein injection of SCL and A549 into SCID mice (n=10 per group, 20±2.5 g) under Nembutal anesthesia (50 mg/ml). At a subcutaneous inoculation concentration of 1x10 6 cells per mouse, the SCL consistently produced subcutaneous tumors. At an intravenous injection concentration of 2x10 6 cells per mouse, the SCL and A549 cells consistently produced intravenous and lung tumors.…”

“…At a subcutaneous inoculation concentration of 1x10 6 cells per mouse, the SCL consistently produced subcutaneous tumors. At an intravenous injection concentration of 2x10 6 cells per mouse, the SCL and A549 cells consistently produced intravenous and lung tumors. The mice were sacrificed, and the tumors and the organs were quickly isolated and excised on the appropriate days after intravenous injection.…”

“…Recently, the existence of not only myofibroblast-like cells, but also endothelial-like cells, in the endarterectomized tissues from patients with CTEPH has been demonstrated (4)(5)(6). Moreover, our recent study suggested that these myofibroblast-like cells might release substances that promote the endothelial-mesenchymal transition (EnMT) and/or induce EC dysfunction (7).…”

Epidemiology and Pathophysiology of Chronic Thromboembolic Pulmonary Hypertension: Risk Factors and Mechanisms

“…22 One study showed that multipotent mesenchymal progenitor cells have been found within endarterectomized tissue; these could contribute to the fibrosis and stabilization of the clot. 30 Vascular changes were noted not only in large vessels directly affected by clots but also in small distal arteries. 21 This aspect of the disease is of crucial importance, as patients with primarily distal disease are considered poor surgical candidates.…”

Pulmonary Microvascular Remodeling after Balloon Pulmonary Angioplasty in a Patient with Chronic Thromboembolic Pulmonary Hypertension

“…It is possible that the degree of microvascular remodeling varies among lobes in the same patient. Another possibility is the difference in the type of cells constituting the vascular remodeling and mechanisms underlying CTEPH and PAH (7,8). Distal pulmonary vasculopathy in patients with CTEPH develops in both the occluded and non-occluded pulmonary vascular bed and is characterized by lesions considered typical for idiopathic PAH pathologically (9).…”