Precursor cells in human pulmonary hypertension

产品说明：本申请旨在研究肺动脉高压（PAH）患者肺组织中前体细胞的存在和激活机制，PAH是一组没有治愈性治疗方案的致命疾病。人们越来越多地认识到，血管增生性病变中的细胞具有抗血管增生性，近年来，主要在动物模型中，已经产生了关于骨髓（BM）源性前体细胞对血管重塑的贡献的大量信息，但尚不清楚BM源性和驻留前体细胞是否有助于人类患者的血管闭塞性PAH。目前的文献也缺乏对PAH中前体细胞激活机制的详细了解。在我们的动物模型SU 5416/慢性缺氧（SuHX）的初步数据表明，前体细胞表达各种干细胞和祖细胞标志物的血管闭塞性病变和周围积累，这些细胞中的一些可能是自我更新的干细胞。在PAH患者的人体组织中，我们检测到这些干细胞和祖细胞标志物染色阳性的细胞分布与SuHX模型相似。该建议是我们动物工作的延伸，通过免疫荧光染色和共聚焦显微镜检测干细胞和祖细胞标志物、活化/分化因子，以及通过体外血管生成测定和细胞培养检测人PAH肺组织和血清的血管生成和前体活化潜力。虽然动物模型对于研究疾病机制和治疗策略很重要，但有必要检查人体组织标本以增加我们动物数据的转化价值。

DESCRIPTION: This application aims to investigate the presence and the activation mechanisms of precursor cells in lung tissue of patients with pulmonary arterial hypertension (PAH), a group of deadly diseases without curative treatment options. It is increasingly acknowledged that the cells in the angioproliferative lesions are apoptosis-resistant, and recent years have generated substantial information about the contribution of bone marrow (BM)-derived precursor cells to vascular remodeling mainly in animal models, but it is unknown whether or not BM-derived and resident precursor cells contribute to angioobliterative PAH in human patients. The current literature also lacks a detailed understanding of the mechanisms of precursor cell activation in PAH. Preliminary data in our animal model of SU5416/chronic hypoxia (SuHX) indicates that precursor cells expressing various stem and progenitor cell markers accumulate in and around angioobliterative lesions and that some of these cells may be self-renewing stem cells. In human tissue of PAH patients, we have detected a similar distribution of cells staining positive for these stem and progenitor cell markers as in the SuHX model. This proposal is an extension of our animal work to detect stem and progenitor cell marker, activation/differentiation factors by immunofluorescence staining and confocal microscopy, as well as angiogenic and precursor activation potential of human PAH lung tissue and serum by in vitro angiogenesis assay and cell culture. Although animals models are important to investigate disease mechanisms and treatment strategies, it is necessary to examine human tissue specimens to increase the translational value of our animal data.