Marrow Stromal Cell Homing to the Lung in Emphysema

肺气肿中骨髓基质细胞归巢至肺

• 批准号: 6968006
• 负责人: JUDD E SHELLITO
• 金额: $ 35.53万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-12-01 至 2009-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6968006
• 关键词: bone marrow; cell differentiation; cell migration; cell population study; cell transplantation; chemokine; chemotaxis; disease /disorder model; elastases; emphysema; genetically modified animals; laboratory rat; lung transplantation; nonhuman therapy evaluation; respiratory disease /disorder therapy; stromal cells; tissue /cell culture; vascular cell adhesion molecule

Chronic Obstructive Pulmonary Disease (Chronic Bronchitis & Emphysema) ranks 4th among the leading causes of mortality in the United States. Emphysema is manifest histologically as the destruction of alveolar walls without significant fibrosis. Restoration of respiratory function in the emphysematous lung may be possible by expanding alveolar surface area through the use of adult bone marrow-derived stromal cells for tissue regeneration in the distal lung. Injury appears to increase the prevalence of marrow stromal cells (MSCs) in the lung after systemic administration. However, unenhancecl lung engraftment of MSCs is limited, making significant tissue regeneration unlikely at current levels of engraftment. Therefore, before the utility of MSCs can be fully tested, we need to evaluate mechanisms by which MSCs are recruited to, and engraft in, the injured lung. Our Hypothesis is that a specific subpopulation of MSCs will optimally engraft in the emphysematous lung via a multi-step process involving both vascular adhesion and chemotaxis. The Specific Aims of this application are: Specific Aim 1: To compare engraftment of MSC subpopulations in the elastase model of emphysema and to evaluate the implantation process. Specific Aim 2: To investigate the role of endothelial adhesion in MSC homing to the lung. Specific Aim 3: To evaluate the hypothesis that augmenting chemokine-directed MSC migration will increase engraftment in the lung. Specific Aim 4: To determine the morphological and functional outcomes of optimized MSC delivery to the emphysematous lung. The lung engraftment potential of different MSC subpopulations identified will be tested in the in vivo elastase model of emphysema. Differentiation of engrafted cells will be determined and the role of cell fusion defined. Integrin- & selectin-mediated vascular adhesion, chemokine signaling pathways and mechanics of engraftment will be explored in order to augment MSC delivery to the lung. We will then evaluate the morphologic and functional impact of optimized delivery of bone marrow-derived stromal cells to the alveolar wall in the emphysematous lung. These studies will expand our understanding of the biology of MSCs & methods to improve recruitment to the lung, hopefully leading to novel therapies for emphysema.

慢性阻塞性肺疾病（慢性支气管炎和肺气肿）在美国死亡率的主要原因中排名第四。肺气肿在组织学上表现为肺泡壁的破坏，但没有明显的纤维化。肺气肿肺的呼吸功能的恢复可能是通过使用成人骨髓来源的基质细胞在远端肺组织再生扩大肺泡表面积。损伤似乎增加了骨髓基质细胞（MSC）在肺中的流行率， 局然而，MSC的未增强的肺植入是有限的，使得在当前的植入水平下不可能实现显著的组织再生。因此，在充分测试MSC的效用之前，我们需要评估MSC被招募并移植到受损肺中的机制。我们的假设是，一个特定的亚群的间充质干细胞将最佳地植入肺气肿肺通过一个多步骤的过程，涉及血管粘附和趋化性。本申请的具体目的是：具体目的1：比较肺气肿弹性蛋白酶模型中MSC亚群的植入并评价植入过程。具体目标2：研究内皮细胞粘附在MSC归巢至肺中的作用。具体目标3：评估增强趋化因子指导的MSC迁移将增加肺中的植入的假设。具体目标4：确定优化MSC递送至肺气肿肺的形态和功能结果。将在肺气肿的体内弹性蛋白酶模型中测试所鉴定的不同MSC亚群的肺植入潜力。将确定移植细胞的分化，并确定细胞融合的作用。整合素和选择素介导的血管粘附，趋化因子信号通路和植入机制将被探索，以增加MSC输送到肺。然后，我们将评估骨髓源性基质细胞优化输送到肺气肿肺的肺泡壁的形态和功能的影响。这些研究将扩大我们对间充质干细胞生物学的理解，以及改善肺招募的方法，有望导致肺气肿的新疗法。