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

描述(申请人提供)：肺气肿是一种常见的肺部疾病，定义为永久性的空间扩大，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。关于肺气肿全身性疾病的机制以及它们对肺部疾病的影响(如果有的话)，人们知之甚少。吸烟多年后临床表现出的肺损害被归因于蛋白酶-抗蛋白酶失衡、慢性炎症、氧化应激和肺泡细胞过度死亡，失去支持肺泡单位的肺毛细血管。在急性骨骼肌、心肌和脑缺血模型中，我们证明了脂肪基质中包含的多能细胞，称为脂肪干细胞或基质细胞，促进了毛细血管的生长，限制了缺血组织的损伤，这些有益的作用是由血管生成和抗凋亡的旁分泌因子介导的。考虑到获得这些干细胞的可行性，不需要或有限的体外扩增，我们测试了脂肪干细胞对香烟烟雾诱导的小鼠肺气肿的影响。这种形式的再生治疗结果是保存了肺泡表面积，并显著保护了骨髓免受烟雾对多个祖细胞系的数量和周期的抑制作用。因此，我们提出了一个新的假设，即脂肪干细胞治疗将通过减少肺结构细胞死亡和减少骨髓来源的祖细胞的损失来改善吸烟引起的肺泡结构丢失。为了测试这一治疗肺气肿的新方法，并进一步了解肺和骨髓在肺气肿发生发展中的相互作用，我们集中在3个具体目标上：1.确定脂肪干细胞限制香烟烟雾诱导的小鼠肺气肿的有效性；2.确定脂肪干细胞治疗对香烟烟雾诱导的骨髓来源的祖细胞丢失的影响，并确定其在肺气肿发生发展中的重要性；3.建立脂肪干细胞分泌的旁分泌因子VEGF、HGF和TSG-6在抑制脂肪干细胞暴露诱导的肺破坏和骨髓发育不良中的作用。我们已经组建了一个拥有肺气肿病理生物学、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，以调查拟议的综合研究计划。如果完成，这项工作将在相关的肺气肿模型中确定成人脂肪干细胞治疗的有效性、最佳方法和机制，从而被普遍接受，并将加速其作为COPD潜在治疗方法的实施。 公共卫生相关性：在这里，我们提出了一项新的研究，以探讨脂肪基质或干细胞治疗改善吸烟引起的小鼠肺气肿的有效性和机制。我们是唯一有资格进行这项研究的人，因为我们在香烟烟雾所致肺损伤的研究以及成人脂肪干细胞在涉及毛细血管床凋亡的其他疾病的基础和翻译应用方面拥有丰富的经验。此外，通过研究脂肪干细胞如何将骨髓从吸烟的有害影响中拯救出来，这项工作将研究香烟诱导损伤的潜在新机制，包括骨髓来源的祖细胞的损失。因此，我们的工作有望为治疗策略提供理论基础，该策略涉及在COPD患者中使用伦理上可接受和容易获得的干细胞，这可能会扩展到其他疾病，在这些疾病中，骨髓祖细胞参与是关键。

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. PUBLIC HEALTH RELEVANCE: Here we propose a new investigation of the efficacy of and mechanisms underlying the treatment with adipose stromal or stem cells to ameliorate emphysema induced by cigarette smoke in mice. We are uniquely qualified to conduct this study, since we have a combined experience in the research of cigarette smoke-induced lung injury, and basic and translational applications of adult adipose stem cells to other diseases that involve apoptosis of capillary vascular beds. In addition, by studying how adipose stem cells rescue the bone marrow from the deleterious effects of cigarette smoking, this work will study a potentially novel mechanism of cigarette-induced injury, involving the loss of bone marrow-derived progenitor cells. Our work is therefore expected to provide the rationale for a therapeutic strategy that involves the use of ethically acceptable and easily obtainable stem cells in patients with COPD, which may be extended to other diseases in which bone marrow progenitor cell participation is key.