Direct and Bone-Marrow Mediated Effects of Adipose Stem Cells in Emphysema

脂肪干细胞对肺气肿的直接作用和骨髓介导作用

• 批准号: 8392234
• 负责人: KEITH LEONARD MARCH
• 金额: $ 37.13万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-12-15 至 2015-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8392234
• 关键词: Accounting; Acute; Address; Adipose tissue; Adult; Alveolar; Alveolar Cell; Anti-Inflammatory Agents; Anti-inflammatory; Apoptosis; Apoptotic; Area; Autologous; Autophagocytosis; Biological Preservation; Blood Vessels; Blood capillaries; Bone Marrow; Bone Marrow Cells; Bone Marrow Stem Cell; Cardiovascular system; Cell Death; Cell Therapy; Cells; Cerebral Ischemia; Cerebrum; Cessation of life; Chronic; Chronic Obstructive Airway Disease; Cigarette; Cigarette smoke-induced emphysema; Collaborations; Data; Development; Disease; Distal; Effectiveness; Functional disorder; Future; Genes; Goals; Growth; Growth Factor; Hematopoiesis; Human; Hypocellular Bone Marrow; Inflammation; Injury; Investigation; Label; Lead; Lung; Lung diseases; Maintenance; Mediating; Modeling; Mus; Myocardial; Organ; Oxidative Stress; Patients; Peptide Hydrolases; Perfusion; Play; Predisposition; Property; Protease Inhibitor; Proteins; Pulmonary Emphysema; Qualifying; Research; Role; Signal Transduction; Skeletal Muscle; Smoke; Smoking; Source; Stem cells; Stromal Cells; Suction Lipectomy; Surface; TNF gene; Testing; Therapeutic; Tissues; Transgenic Mice; Transplantation; Vascular Endothelial Growth Factors; Work; alveolar destruction; capillary; cigarette smoke-induced; cigarette smoking; cytokine; experience; lung injury; multidisciplinary; novel; paracrine; prevent; progenitor; programs; protective effect; regenerative; release factor; repaired; stem cell biology; stem cell therapy; tissue repair; vascular bed

DESCRIPTION (provided by applicant): Pulmonary emphysema is a prevalent lung disease defined by permanent enlargement of airspaces, but also associated with systemic effects on organs that include the bone marrow and the cardiovascular system. Little is known about the mechanisms of systemic illness in emphysema and their impact, if any, on the lung disease. The lung destruction, clinically apparent after years of cigarette smoking has been attributed to protease-antiprotease imbalance, chronic inflammation, oxidative stress, and excessive alveolar cell death with loss of pulmonary capillaries that support the alveolar unit. We demonstrated that pluripotent cells contained in adipose stroma, called adipose stem or stromal cells promote capillary growth and limit ischemic tissue damage in models of acute skeletal muscle, myocardial, and cerebral ischemia and these salutary effects are mediated by angiogenic and anti-apoptotic paracrine factors. Given the feasibility of obtaining these stem cells, requiring no or limited ex vivo expansion, we tested the effect of adipose stem cells on cigarette smoke-induced murine emphysema. This form of regenerative treatment resulted in preservation of alveolar surface area and marked protection of the bone marrow from the suppressive effects of smoke on the number and cycling of multiple lineages of progenitor cells. We therefore generated the novel hypothesis that treatment with adipose stem cells will ameliorate the alveolar structural loss induced by cigarette smoking by decreasing lung structural cell death and reducing the loss of bone marrow-derived progenitor cells. To test this novel promising therapy for emphysema and to advance understanding of the crosstalk between the lung and bone marrow in emphysema development, we focused on 3 specific aims: 1. to determine the efficacy of adipose stem cells to limit cigarette smoke-induced murine emphysema; 2. to determine the effect of adipose stem cell treatment on the cigarette smoke-induced bone marrow-derived progenitor cell loss and to establish its importance to the development of emphysema; 3. to establish the role of adipose stem cell-secreted paracrine factors VEGF, HGF, and TSG-6 in the inhibition of lung destruction and of bone marrow hypoplasia induced by adipose stem cell exposure. We have assembled a multidisciplinary team with expertise in emphysema pathobiology, adipose stem cell-, vascular-, and bone marrow stem cell-biology to investigate the proposed comprehensive research plan. If completed, this work will determine the effectiveness, optimal approach, and mechanisms of adult, thus generally ethically accepted, adipose stem cell therapy in a relevant emphysema model, and will accelerate its implementation as a potential therapeutic approach in COPD.

描述（由申请人提供）：肺部肺气肿是一种普遍的肺部疾病，该疾病是由空体永久扩大而定义的，但也与包括骨髓和心血管系统在内的器官的全身影响有关。关于肺气肿中系统性疾病的机制及其对肺部疾病的影响（如果有的话）知之甚少。在吸烟多年后，肺部破坏归因于蛋白酶 - 抗蛋白酶不平衡，慢性炎症，氧化应激和过度肺泡细胞死亡，且肺毛细血管失去支持肺泡单位。我们证明，脂肪基质中包含的多能细胞称为脂肪干或基质细胞可促进毛细血管生长，并限制急性骨骼肌，心肌和脑缺血模型的缺血组织损伤，这些可观的效应是由血管疾病和抗质细胞性副刺激因子介导的。 。鉴于需要获得这些干细胞的可行性，不需要或有限的离体膨胀，我们测试了脂肪干细胞对香烟烟雾诱导的鼠肺气肿的影响。这种再生治疗形式导致保存牙槽表面积，并明显保护骨髓免受烟雾对祖细胞多个谱系数量和循环的抑制作用。因此，我们产生了一个新的假设，即用脂肪干细胞的治疗将通过减少肺结构细胞死亡并减少骨髓衍生祖细胞的丧失来改善吸烟引起的肺泡结构损失。为了测试这种新颖的有前途的肺气肿疗法，并提高对肺骨髓发育中肺和骨髓之间的串扰的了解，我们集中在3个特定目标上：1。确定脂肪干细胞限制香烟烟雾诱导的鼠类渗透性的功效; 2。确定脂肪干细胞处理对香烟烟雾引起的骨髓衍生的祖细胞损失的影响，并确定其对肺气肿发展的重要性； 3。为了确定脂肪干细胞分泌的旁分泌因子VEGF，HGF和TSG-6在抑制肺部破坏和脂肪干细胞暴露引起的骨髓性发育不全中的作用。我们已经组建了一个具有肺气肿病理学，脂肪干细胞，血管和骨髓干细胞生物学专业知识的多学科团队，以研究拟议的综合研究计划。如果完成，这项工作将确定成人的有效性，最佳方法和机制，因此在相关的肺气肿模型中通常在道德上接受，脂肪干细胞疗法，并将加速其作为COPD中潜在治疗方法的实施。