Repair Mechanisms of Adult Mesenchymal Stem Cells in Lung Injury

描述(申请人提供)：在成年生物体中，主要分布在骨髓中的细胞和少量分布在其他器官的细胞具有分化为多种细胞表型的能力。一种损伤组织修复的趋势是将这些祖细胞动员并归巢到损伤部位，并将它们分化为器官实质细胞类型。然而，祖细胞通过分化为肺成纤维细胞也参与了促进纤维化的发生。基于我们和其他人的研究，我们假设骨髓来源的祖细胞可能促进肺修复或纤维化，这取决于损伤的性质和宿主的免疫倾向。在这个项目中，我们建议阐明骨髓来源的干细胞在急性和慢性肺损伤中的作用。我们将在一种新的啮齿动物模型中进行研究，对T-bet基因缺陷小鼠进行博莱霉素慢性治疗，以诱导进行性肺纤维化。因此，我们提出以下假设： 1.对于单次损伤，间充质干细胞通过调节炎症反应促进损伤肺的有效修复，有利于一过性纤维化的形成，是重塑和分化为肺实质细胞所必需的。 2.长期或反复的肺损伤会引发一种不良的适应性修复反应，在这种反应中，间充质干细胞通过支持持续的Th2型免疫反应，并定位于肺内，分化为直接导致纤维化的成纤维细胞，从而促进纤维化的形成。 3.CD4+T淋巴细胞持续的Th2偏向促进了对肺损伤的不良适应反应。给偏向Th2的动物注射间充质干细胞会加重对博莱霉素的纤维化反应。 为了检验这些假设，我们提出了以下具体目标： 1.采用进行性肺纤维化动物模型，比较单次和多次气管内滴注博莱霉素对肺组织的影响。 2.探讨骨髓间充质干细胞移植对博莱霉素反复肺损伤的治疗作用。3.在体外和体内研究趋化因子(SDF-1)和Th2细胞因子(IL-4和IL-13)和TGFf31在持续损伤后骨髓间充质干细胞在肺内定位、增殖和分化过程中的作用。

DESCRIPTION (provided by applicant): In adult organisms, cells localized primarily in the bone marrow and in low number in other organs have the ability to differentiate into multiple cell phenotypes. One current of repair of injured tissue invokes mobilization and homing of these progenitor cells to sites of injury and their differentiation into organ parenchymal cell types. However, progenitor cells have also been implicated in promoting fibrogenesis by differentiating into lung fibroblasts. Based on our and others studies, we hypothesize that bone marrow derived progenitor cells may promote either lung repair or fibrosis, depending on the nature of the injury and the immune proclivity of the host. In this project we propose to clarify the roles of bone marrow derived stem cells in acute and chronic lung injury. We will conduct studies in a novel rodent model, a genetically modified T-bet deficient mice will be treated chronically with bleomycin to induce progressive pulmonary fibrosis. Therefore, we propose the following hypothesis: 1. In response to a single episode of injury, mesenchymal stem cells contribute to effective repair of the injured lung by modulating the inflammatory response, favoring transient fibrogenesis essential to remodeling and differentiating into lung parenchymal cells. 2. Prolonged or repeated lung injury provokes a maladaptive repair response in which mesenchymal stem cells promote fibrogenesis by favoring a persistent Th2 type immune response and by localizing in the lungs and differentiating into fibroblasts that contribute directly to the fibrosis. 3. A persistent Th2 bias of CD4+ T lymphocytes promotes a maladaptive response to lung injury. Administration of mesenchymal stem cells to Th2 biased animals will exaggerate the fibrotic response to bleomycin . To test these hypothesis, we propose the following specific aims: 1. Using an animal model of progressive pulmonary fibrosis, to compare responses of the lungs to single and multiple intratracheal instillations of bleomycin. 2. To determine effects of mesenchymal stem cell transfer on repeated bleomycin induced lung injury. 3. In vitro and in vivo to determine the role of chemoattractant factors (SDF-1) and Th2 cytokines (IL-4 and IL-13) and TGFf31, in the processes of localization, proliferation and differentiation of bone marrow derived mesenchymal stem cells in the lungs after continues injury.