Mesenchymal Stem Cells and Pulmonary Hypertension

间充质干细胞和肺动脉高压

• 批准号: 7571584
• 负责人: Stella Kourembanas
• 金额: $ 42.25万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-01 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7571584
• 关键词: Address; Adopted; Adult; Affect; Age; Animal Model; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Blood Platelets; Blood Vessels; Bone Marrow; Bone Marrow Stem Cell; CXCR4 Receptors; Cardiac; Cell Proliferation; Cells; Cellular Morphology; Cessation of life; Characteristics; Chronic; Coagulants; Data; Deposition; Development; Dilatation - action; Disease; Engineering; Engraftment; Epithelial; Epithelial Cells; Extracellular Matrix; Functional disorder; Genes; Goals; Growth Factor; Home environment; Homing; Human; Hyperplasia; Hypoxia; Immigration; Infarction; Inflammation; Laboratories; Life; Lung; Lung Inflammation; Medical; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Mus; Patients; Phenotype; Process; Pulmonary Hypertension; Pulmonary Surfactant-Associated Protein C; Pulmonary artery structure; Quality of life; Reporting; Research Design; Research Personnel; Right Ventricular Hypertrophy; Smooth Muscle Myocytes; Stem cell transplant; Stem cells; Stimulus; Structure of jugular vein; Testing; Therapeutic; Transgenes; Transgenic Mice; Type II Epithelial Receptor Cell; Vascular remodeling; Vasodilator Agents; Ventricular; Wound Healing; base; chemokine; cytokine; falls; heme oxygenase-1; human disease; improved; in vivo; macrophage; mouse model; neonate; overexpression; paracrine; pressure; promoter; protective effect; repaired; response; transdifferentiation; vasoconstriction

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.

描述（由申请人提供）：肺动脉高压（PHtn）是一种危及生命的疾病，可影响从新生儿到成人的所有年龄段。这种疾病的标志是肺小动脉血管收缩增加和血管壁重塑，其特征在于内膜增生、中膜中平滑肌细胞层过多和细胞外基质沉积。虽然肺动脉高压患者的生存率和生活质量有所改善，但这种疾病尚无治愈方法。当前医学治疗的主要形式福尔斯分为几种治疗形式，包括使用血管扩张剂、抗凝剂、抗血小板剂、抗炎和血管重塑治疗。缺氧是已知的PHtn发展的主要或次要刺激，暴露于缺氧的各种动物模型发展为人类疾病的特征性肺和心脏表现。我们研究了基因工程骨髓间充质干细胞（MSC）表达的细胞保护基因，血红素加氧酶-1（HO-1）治疗缺氧诱导的PHtn的治疗潜力。使用我们和其他人已经表征的缺氧诱导的肺动脉高压的小鼠模型，我们先前报道了具有由表面活性蛋白C（SPC）启动子（SHO 1）驱动的肺特异性HO-1过表达的转基因小鼠不会响应于缺氧暴露而发展PHtn。与野生型动物相比，HO-1缺陷的小鼠对缺氧具有适应不良反应，并且除了肺动脉高压之外，它们还发生右心室扩张和梗死。我们已经产生的初步数据显示，通过颈静脉将过表达HO-1的MSC移植到肺中可以逆转HO-1缺陷小鼠中缺氧诱导的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，以便我们能够开发用于治疗人类这种疾病的合理疗法。该提案的具体目的是：（1）研究HO-1是否是MSC对肺动脉高压发展的保护作用所必需的，（2）研究MSC在肺中归巢和植入的机制，以及（3）研究MSC在缺氧肺中修复机制的基础。