Mesenchymal Stem Cells and Pulmonary Hypertension

间充质干细胞和肺动脉高压

• 批准号: 7386618
• 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/7386618
• 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; Condition; 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; Pathological Dilatation; Patients; Phenotype; Process; Protein C; Protein Overexpression; Pulmonary Hypertension; 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; paracrine; pressure; promoter; protective effect; repaired; response; surfactant; 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，可以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和血管壁重塑增加，其特征是内膜增生、中层平滑肌细胞层过多和细胞外基质沉积。尽管肺动脉高压患者的生存率和生活质量有所改善，但这种疾病无法治愈。当前医学治疗的支柱分为多种治疗形式，包括使用血管扩张剂、抗凝剂、抗血小板剂、抗炎和血管重塑疗法。缺氧是已知的 PHtn 发生的主要或继发刺激因素，暴露于缺氧的各种动物模型会出现人类疾病特征的肺部和心脏表现。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) 治疗缺氧诱导的 PHtn 的治疗潜力。使用我们和其他人描述的缺氧诱导肺动脉高压小鼠模型，我们之前报道过，由表面活性蛋白 C (SPC) 启动子 (SHO1) 驱动的肺特异性 HO-1 过度表达的转基因小鼠不会发展为 PHtn应对缺氧暴露。缺乏 HO-1 的小鼠对缺氧有适应不良反应，除了肺动脉高压之外，与野生型动物相比，它们还会出现右心室扩张和梗塞。我们已经生成的初步数据表明，通过颈静脉将过度表达 HO-1 的 MSC 移植到肺部，可以逆转 HO-1 缺陷小鼠缺氧诱导的 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，以便我们能够开发出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 MSC 对肺动脉高压发展的保护作用是否需要 HO-1，(2) 研究 MSC 归巢和在肺中植入的机制，以及 ( 3）探讨缺氧肺中MSC修复机制的基础。