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

描述（由申请人提供）：肺气肿是一种常见的肺部疾病，以空气空间的永久性扩大为特征，但也与包括骨髓和心血管系统在内的器官的系统性影响有关。关于肺气肿的全身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。多年吸烟后临床表现明显的肺损害归因于蛋白酶-抗蛋白酶失衡、慢性炎症、氧化应激和肺泡细胞过度死亡，并伴有支持肺泡单位的肺毛细血管的丧失。我们证明，在急性骨骼肌、心肌和脑缺血模型中，脂肪基质中含有的多能细胞，称为脂肪干细胞或基质细胞，可促进毛细血管生长并限制缺血性组织损伤，这些有益作用是由血管生成和抗凋亡旁分泌因子介导的。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导致肺泡表面积的保存，并显著保护骨髓免受烟雾对多系祖细胞数量和循环的抑制作用。因此，我们提出了一个新的假设，即脂肪干细胞治疗可以通过减少肺结构细胞死亡和减少骨髓源祖细胞的损失来改善吸烟引起的肺泡结构损失。为了测试这种治疗肺气肿的新方法，并进一步了解肺气肿发展过程中肺和骨髓之间的串扰，我们专注于三个具体目标：1。探讨脂肪干细胞对香烟所致小鼠肺气肿的抑制作用；2. 探讨脂肪干细胞治疗对香烟所致骨髓源性祖细胞丢失的影响，并确定其在肺气肿发生中的重要性；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全中的作用。我们已经组建了一个多学科团队，在肺气肿病理生物学、脂肪干细胞、血管和骨髓干细胞生物学方面具有专业知识，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，从而在伦理上被普遍接受，脂肪干细胞治疗相关肺气肿模型，并将加速其作为COPD潜在治疗方法的实施。

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.