Precursor cells in human pulmonary hypertension

描述：本应用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是一组致命的疾病，没有根治的治疗方案。越来越多的人认识到血管增生性病变中的细胞是抗凋亡的，近年来主要在动物模型中产生了大量关于骨髓来源的前体细胞在血管重构中的作用的信息，但尚不清楚骨髓来源的前体细胞和常驻的前体细胞是否参与了人类患者的血管闭塞性肺高压。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聚集在血管闭塞病变内和周围，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，我们检测到与SuHX模型中类似的干细胞和祖细胞标记物阳性的细胞分布。这一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、激活/分化因子，以及通过体外血管生成试验和细胞培养检测人PAH肺组织和血清的血管生成和前体激活潜能。虽然动物模型对研究疾病机制和治疗策略很重要，但有必要检查人类组织样本，以增加动物数据的翻译价值。 公共卫生相关性：肺动脉高压(PAH)是一种导致患者过早死亡的致残性疾病，由于目前的治疗方法并不针对导致肺血管闭塞的血管细胞的异常生长，因此到目前为止还没有找到治愈的方法。近年来，已有证据表明具有自我更新或替代功能的细胞，即所谓的前体细胞，可能有助于人类PAH血管构筑的变化，但这些细胞(骨髓或肺)的来源及其在人类肺组织中的作用机制尚不完全清楚。这项应用将更详细地研究人类PAH组织样本中干细胞和祖细胞的存在，并通过组织学和体外方法关注激活机制，目的是寻找新的靶点来抑制肺血管内异常细胞的生长，从而提高PAH患者的存活率。(摘要结束)

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)