Mesenchymal Stem Cells and Pulmonary Hypertension

描述(申请人提供)：肺动脉高压(PHTN)是一种危及生命的疾病，可影响从新生儿到成年人的各个年龄段。这种疾病的特点是肺小动脉血管收缩增加和管壁重构，其特征是内膜增生，中层平滑肌细胞层过多，细胞外基质沉积。尽管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。目前的医学治疗主要分为几种治疗形式，包括使用血管扩张剂、抗凝剂、抗血小板药、抗炎和血管重塑疗法。已知低氧是PHtN发生的主要或次要刺激因素，暴露在低氧环境下的各种动物模型会出现人类疾病特有的肺和心脏表现。我们研究了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)治疗缺氧性PHtN的可能性。使用我们和其他人描述的缺氧性肺动脉高压的小鼠模型，我们之前报道了由表面活性蛋白C(SPC)启动子(SHO1)驱动的肺特异高表达HO-1的转基因小鼠不会对低氧暴露产生PHtn。与野生型动物相比，HO-1基因缺失的小鼠对低氧有不适应的反应，除了肺动脉高压外，它们还会出现右心室扩张和梗塞。我们已经产生了初步的数据表明，通过颈静脉将高表达HO-1的MSC移植到肺内可以逆转HO-1缺陷小鼠的缺氧诱导的PHtn。我们的总体目标是了解MSC在低氧小鼠模型中抑制/逆转肺动脉高压发展的机制，以便我们能够开发合理的治疗方法来治疗人类这种疾病。本研究的具体目的是：(1)探讨HO-1是否参与MSC对肺高压的保护作用；(2)探讨MSC在肺内归巢和植入的机制；(3)探讨MSC在低氧肺中修复机制的基础。

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.