Dept. of Medicine, Univ. of California, San Diego, La Jolla, 92093-0725, USA.
Am J Physiol Cell Physiol. 2010 May;298(5):C1217-25. doi: 10.1152/ajpcell.00416.2009. Epub 2010 Feb 24.
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.
导致纤维血管瘢痕形成和肺血管重塑从而导致慢性血栓栓塞性肺动脉高压（CTEPH）的因素尚不清楚。本研究调查了多能祖细胞和肌成纤维细胞对 CTEPH 发展和进展的潜在贡献。对 CTEPH 患者的内膜切除术组织进行的组织学检查确定了明显的新生内膜形成。从这些组织中分离出的细胞存在形态异质性，包括网络样生长模式和集落形成单位成纤维细胞样集落（CFU-F）的形成。细胞通常共表达中间丝波形蛋白和平滑肌α-肌动蛋白。通过免疫荧光和荧光激活细胞分选（FACS）对细胞表面标志物进行特征分析，这些标志物是间充质祖细胞的典型标志物；细胞>99% CD44(+) CD73(+)、CD90(+)、CD166(+)；>80% CD29(+)；45-99% CD105(+)；CD34(-)和 CD45(-)。细胞能够进行成脂和成骨分化，分别通过油红 O 和茜素红染色确定。此外，通过 FACS 分选得到的 Stro-1(+)细胞（骨髓基质细胞的标志物，占 4.2%）也具有成脂和成骨分化的能力。总之，本研究首次鉴定出内膜切除术组织中主要存在的肌成纤维细胞表型，广泛参与血管病变/血栓形成。这种细胞可能来源于外膜成纤维细胞的转分化或间充质祖细胞的分化。稳定血栓形成的独特微环境可能是刺激这种细胞变化的一个因素。这些发现对于确定未来在肺动脉高压的新型和急需的治疗方法的开发方面的研究至关重要。
