Repair Mechanisms of Adult Mesenchymal Stem Cells in Lung Injury

描述（由申请方提供）：在成年生物体中，主要位于骨髓中的细胞和其他器官中的少量细胞具有分化为多种细胞表型的能力。损伤组织的修复的一个电流引起这些祖细胞的动员和归巢到损伤部位并分化成器官实质细胞类型。然而，祖细胞还通过分化成肺成纤维细胞而参与促进纤维形成。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。本课题旨在阐明骨髓源性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，一种遗传修饰的T-bet缺陷小鼠将用博来霉素长期治疗以诱导进行性肺纤维化。因此，我们提出如下假设： 1.在对单次损伤的反应中，间充质干细胞通过调节炎症反应，促进对重塑和分化成肺实质细胞至关重要的瞬时纤维化，从而有助于有效修复受损的肺。 2.长期或重复的肺损伤引起适应不良的修复反应，其中间充质干细胞通过促进持续的Th 2型免疫反应和通过定位于肺中并分化成直接促成纤维化的成纤维细胞来促进纤维化。 3. CD 4 + T淋巴细胞的持续Th 2偏好促进了对肺损伤的适应不良反应。向Th 2偏向的动物施用间充质干细胞将夸大对博来霉素的纤维化反应。 为了检验这些假设，我们提出了以下具体目标： 1.使用进行性肺纤维化动物模型，比较肺对单次和多次肺内滴注博来霉素的反应。 2.目的探讨骨髓间充质干细胞移植对博莱霉素诱导的重复性肺损伤的治疗作用。3.体外和体内研究趋化因子（SDF-1）、Th 2型细胞因子（IL-4和IL-13）和TGF-β 1在持续性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.