Precursor cells in human pulmonary hypertension

描述：本应用程序旨在研究肺动脉高压（PAH）患者肺组织中前体细胞的存在及其激活机制，PAH是一组无法治愈的致命疾病。越来越多的人认识到血管增殖性病变中的细胞具有抗凋亡能力，近年来主要在动物模型中产生了大量关于骨髓（BM）来源的前体细胞对血管重塑的贡献的信息，但尚不清楚骨髓来源的前体细胞和常驻前体细胞是否有助于人类患者血管闭塞性多环芳烃。目前的文献也缺乏对PAH中前体细胞活化机制的详细了解。我们在SU5416/慢性缺氧（SuHX）动物模型中的初步数据表明，表达各种干细胞和祖细胞标记的前体细胞在血管闭塞病变内和周围积聚，其中一些细胞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记物呈阳性的细胞分布与SuHX模型相似。本课题是我们动物实验的延伸，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，激活/分化因子，以及通过体外血管生成实验和细胞培养检测人多环芳烃肺组织和血清的血管生成和前体激活电位。虽然动物模型对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的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. PUBLIC HEALTH RELEVANCE: Pulmonary Arterial Hypertension (PAH) is a crippling disease leading to early death of the patients and as current therapies do not target the abnormal growth of vascular cells obliterating pulmonary vessels, a curative treatment has not been found so far. Over the past years, evidence has been generated that cells with self-renewal or replacement features, so called precursor cells, may contribute to the changes in vascular architecture in human PAH, but the origin of these cells (bone marrow or lung) and their mechanism of action in the human lung tissue are incompletely understood. This application will investigate the presence of stem and progenitor cells more detailed in human PAH tissue samples and pay attention to activation mechanisms by histological and in vitro methods with the goal of finding novel targets to inhibit the abnormal cell growth in the lung vasculature and thereby increase survival of PAH patients. (End of Abstract)