Repair Mechanisms of Adult Mesenchymal Stem Cells in Lung Injury

描述（由申请人提供）：在成年生物体中，主要定位于骨髓和少量其他器官的细胞具有分化成多种细胞表型的能力。一种损伤组织的修复需要这些祖细胞的动员和归巢到损伤部位，并分化为器官实质细胞类型。然而，祖细胞也参与通过分化成肺成纤维细胞促进纤维形成。根据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。在本项目中，我们拟阐明骨髓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，一种基因修饰的T-bet缺陷小鼠将被博来霉素长期治疗以诱导进行性肺纤维化。因此，我们提出以下假设：

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.