Mesenchymal Stem Cells and Pulmonary Hypertension

描述（由申请人提供）：肺动脉高压（PHtn）是一种危及生命的疾病，可影响所有年龄段，从新生儿到成年人。这种疾病的标志是肺小动脉血管收缩增加和血管壁重塑，其特征是内膜增生，介质中平滑肌细胞层过多，细胞外基质沉积。虽然肺动脉高压患者的生存和生活质量有所改善，但这种疾病无法治愈。目前主要的医学治疗分为几种形式的治疗，包括使用血管扩张剂、抗凝血剂、抗血小板剂、抗炎和血管重塑疗法。缺氧是已知的PHtn发育的主要或次要刺激因素，暴露于缺氧的各种动物模型都出现了人类疾病特有的肺部和心脏表现。我们研究了用表达细胞保护基因血红素加氧酶-1 （HO-1）的基因工程骨髓间充质干细胞（MSC）治疗缺氧诱导的PHtn的治疗潜力。利用我们和其他人已经描述过的缺氧诱导肺动脉高压小鼠模型，我们之前报道过，由表面活性剂蛋白C （SPC）启动子（SHO1）驱动的HO-1在肺部特异性过表达的转基因小鼠在缺氧暴露时不会产生PHtn。与野生型动物相比，HO-1缺乏的小鼠对缺氧有适应性不良反应，除了肺动脉高压外，它们还会出现右心室扩张和梗死。我们的初步数据显示，将过表达HO-1的间充质干细胞经颈静脉移植到肺中可以逆转缺氧诱导的HO-1缺失小鼠的PHtn。我们的总体目标是了解MSC在缺氧小鼠模型中抑制/逆转肺动脉高压发展的机制，以便我们能够开发出治疗人类这种疾病的合理疗法。本课题的具体目的是：(1)研究MSC对肺动脉高压形成的保护作用是否需要HO-1的参与；(2)研究MSC在肺内的归巢和植入机制；(3)研究缺氧肺中MSC修复机制的基础。

DESCRIPTION (provided by applicant): Pulmonary hypertension (PHtn) is a life-threatening condition that can affect all ages, from neonates to adults. The hallmark of this disorder is increased pulmonary arteriolar vasoconstriction and vessel wall remodeling characterized by intimal hyperplasia, excess smooth muscle cell layers in the media, and deposition of extracellular matrix. Although the survival and quality of life has improved in patients with pulmonary hypertension, there is no cure for this disease. The mainstay of current medical treatment falls into several forms of therapy, including the use of vasodilators, anti-coagulants, anti-platelet agents, anti- inflammatory and vascular-remodeling therapies. Hypoxia is a known primary or secondary stimulus for the development of PHtn and various animal models exposed to hypoxia develop the pulmonary and cardiac manifestations that are characteristic of human disease. We have investigated the therapeutic potential of treating hypoxia-induced PHtn with genetically-engineered bone marrow-derived mesenchymal stem cells (MSC) expressing the cytoprotective gene, heme oxygenase-1 (HO-1). Using a mouse model of hypoxia- induced pulmonary hypertension that we and others have characterized, we had previously reported that transgenic mice with lung-specific overexpression of HO-1 driven by the surfactant protein C (SPC) promoter (SHO1) do not develop PHtn in response to hypoxic exposure. Mice deficient in HO-1 have a maladaptive response to hypoxia and in addition to pulmonary hypertension, they develop right ventricular dilatation and infarction compared to wild type animals. We have generated preliminary data showing that transplantation of MSC over-expressing HO-1 via the jugular vein into the lung could reverse hypoxia-induced PHtn in mice deficient in HO-1. Our overall goal is to understand the mechanisms by which MSC inhibit /reverse the development of pulmonary hypertension in the hypoxic mouse model so that we can develop rational therapies for the treatment of this disease in humans. The specific aims of the proposal are: (1) to investigate whether HO-1 is required for the protective action of MSC on the development of pulmonary hypertension, (2) to investigate the mechanisms of MSC homing and engraftment in the lung, and (3) to investigate the basis of MSC repair mechanisms in the hypoxic lung.