Repair Mechanisms of Adult Mesenchymal Stem Cells in Lung Injury

成体间充质干细胞对肺损伤的修复机制

• 批准号: 8212885
• 负责人: Mauricio Rojas
• 金额: $ 13.34万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-01 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8212885
• 关键词: Acute; Adult; Animal Model; Animals; Area; Bleomycin; Bone Marrow; CD4 Positive T Lymphocytes; CXCR4 Receptors; Cells; Characteristics; Chemotactic Factors; Chronic; Data; Dose; Engineering; Environment; Fibroblasts; Fibrosis; Hamman-Rich syndrome; Hematopoietic Stem Cell Mobilization; Homing; Immune; Immune response; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Injury; Interleukin-13; Interleukin-4; Ligands; Lung; Mediator of activation protein; Mesenchymal Stem Cells; Modeling; Mus; Myelofibrosis; Myelosuppression; Nature; Organ; Organism; Patients; Phenotype; Process; Production; Pulmonary Fibrosis; Rodent Model; Role; Site; Stem cells; Stromal Cell-Derived Factor 1; Testing; Tissues; Wild Type Mouse; base; cell type; cytokine; fibrogenesis; human data; in vivo; indium-bleomycin; injured; injury and repair; lung injury; novel; prevent; progenitor; repaired; response

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.

描述（由申请人提供）：在成体生物体中，主要位于骨髓中且在其他器官中数量较少的细胞具有分化成多种细胞表型的能力。受损组织修复的一种电流会促使这些祖细胞动员并归巢到损伤部位，并将其分化为器官实质细胞类型。然而，祖细胞也通过分化为肺成纤维细胞来促进纤维发生。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，具体取决于损伤的性质和宿主的免疫倾向。在这个项目中，我们建议阐明骨髓干细胞在急性和慢性肺损伤中的作用。我们将在一种新型啮齿动物模型中进行研究，这种转基因 T-bet 缺陷小鼠将长期接受博来霉素治疗以诱导进行性肺纤维化。因此，我们提出以下假设： 1. 针对单次损伤，间充质干细胞通过调节炎症反应，促进对肺实质细胞重塑和分化至关重要的短暂纤维生成，从而有助于有效修复受损肺部。 2.长期或反复的肺损伤会引发适应不良的修复反应，其中间充质干细胞通过支持持续的Th2型免疫反应以及定位在肺部并分化成直接导致纤维化的成纤维细胞来促进纤维形成。 3. CD4+ T 淋巴细胞的持续 Th2 偏向会促进对肺损伤的适应不良反应。对 Th2 倾向的动物施用间充质干细胞会加剧对博莱霉素的纤维化反应。 为了检验这些假设，我们提出以下具体目标： 1.使用进行性肺纤维化的动物模型，比较肺部对单次和多次气管内滴注博来霉素的反应。 2.确定间充质干细胞移植对反复博莱霉素诱导的肺损伤的影响。 3. 体外和体内测定趋化因子（SDF-1）和Th2细胞因子（IL-4和IL-13）和TGFf31在骨髓间充质干细胞定位、增殖和分化过程中的作用持续受伤后肺部。

项目成果

Use of senescence-accelerated mouse model in bleomycin-induced lung injury suggests that bone marrow-derived cells can alter the outcome of lung injury in aged mice.

在博来霉素诱导的肺损伤中使用衰老加速小鼠模型表明，骨髓来源的细胞可以改变老年小鼠肺损伤的结果。

• 发表时间: 2009-07
• 作者: Xu, Jianguo;Gonzalez, Edilson T;Iyer, Smita S;Mac, Valerie;Mora, Ana L;Sutliff, Roy L;Reed, Alana;Brigham, Kenneth L;Kelly, Patricia;Rojas, Mauricio
• 通讯作者: Rojas, Mauricio

Infusion of freshly isolated autologous bone marrow derived mononuclear cells prevents endotoxin-induced lung injury in an ex-vivo perfused swine model.

在离体灌注猪模型中，输注新鲜分离的自体骨髓来源的单核细胞可预防内毒素诱导的肺损伤。

• 发表时间: 2013-03-04
• 影响因子: 7.5
• 作者: Rojas, Mauricio;Parker, Richard E;Thorn, Natalie;Corredor, Claudia;Iyer, Smita S;Bueno, Marta;Mroz, Lyle;Cardenes, Nayra;Mora, Ana L;Stecenko, Arlene A;Brigham, Kenneth L
• 通讯作者: Brigham, Kenneth L

Research in Acute Lung Injury and Pulmonary Fibrosis Modified mesenchymal stem cells using miRNA transduction alter lung injury in a bleomycin model

急性肺损伤和肺纤维化研究中使用 miRNA 转导修饰的间充质干细胞可改变博莱霉素模型中的肺损伤

• 发表时间: 1970-01-01

Aging mesenchymal stem cells fail to protect because of impaired migration and antiinflammatory response.

老化的间充质干细胞由于迁移和抗炎反应受损而无法提供保护。

• DOI: 10.1164/rccm.201306-1043oc
• 发表时间: 2014-04-01
• 期刊: American journal of respiratory and critical care medicine
• 影响因子: 24.7
• 作者: Martha L. Bustos;L. Huleihel;M. Kapetanaki;Christian L Lino;Lyle Mroz;Bryon M Ellis;B. McVerry
• 通讯作者: B. McVerry

Attenuation of early airway obstruction by mesenchymal stem cells in a murine model of heterotopic tracheal transplantation.

在异位气管移植的小鼠模型中间充质干细胞减轻早期气道阻塞。

• DOI: 10.1016/j.healun.2010.09.012
• 发表时间: 2011-03
• 期刊: The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation
• 作者: Grove DA;Xu J;Joodi R;Torres-Gonzales E;Neujahr D;Mora AL;Rojas M
• 通讯作者: Rojas M