Lineage Commitment of Mesenchymal Stem Cell in Allergen-induced Airway Remodeling

间充质干细胞在过敏原诱导的气道重塑中的谱系承诺

• 批准号: 8766670
• 负责人: Peisong Gao
• 金额: $ 24.3万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8766670
• 关键词: Acute; Adult; Affect; Air; Allergens; Arteries; Asthma; Biological; Blood; Blood Circulation; Blood Vessels; Bone Marrow; Bone Marrow Cells; Cell Lineage; Cell Therapy; Cells; Child; Chronic; Chronic Disease; Clinical; Conditioned Culture Media; Connective Tissue; Cytokeratin-14 Staining Method; Cytokeratin-18 Staining Method; Development; Dictyoptera; Disease; E-Cadherin; Epithelial; Epithelial Cells; Epithelium; Etiology; Extracellular Matrix; Extrinsic asthma; Fibroblasts; Future; Growth Factor; Hematopoietic Stem Cell Mobilization; Human; Immigration; Immune; Immunomodulators; In Vitro; Individual; Inflammatory; Lead; Link; Liquid substance; Lung; Lung diseases; Mediating; Mesenchymal Stem Cells; Modeling; Mus; Myofibroblast; Natural regeneration; Organ; Pathogenesis; Play; Population; Prevention; Process; Property; Public Health; Recruitment Activity; Regulatory Element; Role; Signal Pathway; Signal Transduction; Staging; Stem cells; Stream; Structure; System; Tamoxifen; Testing; Tissues; Transforming Growth Factors; Vascular remodeling; Work; airway inflammation; airway remodeling; base; cell motility; cockroach allergen; environmental allergen; improved; inhibitor/antagonist; injured; injured airway; insight; migration; mouse model; nestin protein; neutralizing antibody; novel; paracrine; prevent; public health relevance; receptor; release factor; repaired; research study; response; stem; therapy development; tissue repair

DESCRIPTION (provided by applicant): Asthma is a common chronic illness that affects many children and adults worldwide. A major obstacle to prevention and treatment of asthma has been its diverse etiologies and our inadequate understanding of the biological mechanisms. Recent studies have changed our understanding of asthma as a purely inflammatory disease to a disease in which both inflammatory and structural components are equally involved. Allergen caused epithelial damage in early stages allows environmental allergens access to the airway tissue and may lead to the development of airway remodeling in chronic stages. Therefore, therapies that target the repair of the damaged epithelium in early stages could prevent the pathological airway remodeling and improve asthma control. Mesenchymal stem cells (MSCs) are adult connective tissue progenitor cells with multi-lineage differentiation potential and poten paracrine immunomodulatory properties. MSCs are significantly increased in the lungs after allergen challenge and may participate in airway repair/remodeling. Transforming growth factor ¿1 (TGF¿1) plays an important role in the recruitment of stem/progenitor cells for tissue repair, regeneration, and remodeling in various organs. Our previous studies have provided initial evidence that MSCs and active TGF¿1 signaling are increased in airway in an allergen induced asthma model. Furthermore, conditioned medium (ECM) from cockroach extract challenged epithelium induces the migration of MSCs, while TGF¿1 neutralizing antibody antagonized this migration. Recent studies in vitro have shown that MSCs can differentiate into epithelial cells in the presence of TGF¿1. The stage is thus set to critically evaluate the functional effect on MSCs of TGF¿1signaling in asthma. HYPOTHESIS: Active TGF¿1 is an allergen-activated endogenous messenger that recruits bone marrow-derived MSCs to the injured airways, which differentiate into epithelial cells to repair the damaged epithelium in early stages or into fibroblasts/myofibroblasts contributing to fibrotic airway remodeling in chronic stage of asthma. Aim 1 proposes experiments to determine the role of active TGF¿1 in the recruitment of MSCs to the lung in asthma. We will determine the role of TGF¿1 in migration of MSCs using our Air-Liquid Interface (ALI)-ECM-based cell migration system. We will further examine the recruitment of endogenous nestin+MSCs to the allergen-challenged airways during different stages of asthma using Nes-GFP mice, followed by the examination of the role of TGF¿1 in the recruitment of MSCs using a TGF¿1 neutralizing antibody or TGF-¿ receptor type I (T¿RI) inhibitor. [Aim 2 proposes experiments to track the lineage commitment/differentiation of MSC recruited in lungs through TGF¿1 signaling during acute and chronic stages of asthma]. We have established an inducible MSC lineage tracing mouse model (nestin-CreERT2; ROSA26-EGFP) that we will use to track the lineage commitment of recruited MSCs in airway of acute and chronic allergen-induced models of asthma. This will provide novel insights into the role of TGF-¿1 signaling and MSCs in allergic asthma and offer an opportunity for novel therapies.

描述（由适用提供）：哮喘是一种常见的慢性疾病，影响了全世界的许多儿童和成人。预防和治疗哮喘的主要障碍是其潜水员的病因和我们对生物学机制的理解不足。最近的研究已将我们对哮喘作为纯粹炎症性疾病的理解变成了炎症和结构成分同样涉及的疾病。过敏原会在早期造成上皮损伤，使环境过敏原进入气道组织，并可能导致慢性阶段的气道重塑。因此，靶向修复损坏的上皮的疗法可以防止病理气道重塑并改善哮喘控制。间充质干细胞（MSC）是具有多轮分化潜力的成年结缔组织祖细胞和pot旁分泌免疫调节特性。过敏原挑战后，肺中的MSC显着增加，并且可能参与气道修复/改建。转化生长因子»1（TGF¿1）在茎/祖细胞募集中对各种器官的组织修复，再生和重塑起着重要作用。我们以前的研究提供了初始证据，表明在过敏原诱导的哮喘模型中，气道中的MSC和主动TGF。1。此外，蟑螂提取物的条件培养基（ECM）挑战上皮诱导了MSC的迁移，而TGF？1中和抗体拮抗了这种迁移。最近在体外的研究表明，在TGF¿1的存在下，MSC可以分化为上皮细胞。因此，该阶段被设置为批判性地评估哮喘中TGF¿1SIGNALING的功能效应。 HYPOTHESIS: Active TGF¿ 1 is an allergen-activated endogenous messenger that recruits bone marrow-derived MSCs to the injured airways, which differentiate into epithelial cells to repair the damaged epithelial in early stages or into fibroblasts/myofibroblasts contributing to fibrotic airway remodeling in chronic stages of asthma. AIM 1提案实验，以确定主动TGF。1在哮喘中募集MSC中的作用。我们将使用我们的空气液体界面（ALI）基于ECM的细胞迁移系统来确定TGF¿1在MSC迁移中的作用。我们将在哮喘的不同阶段使用NES-GFP小鼠在哮喘的不同阶段将内源性NESTIN+MSC募集到过敏原挑战的气道中，然后检查TGF¿1在使用TGF招募TGF€1中和TGF-tgf-tgf-tgf-oodor typore I（TGF-typo）I（TGF-typo）I（tgf-quff-typ）中的作用（TGF）。 [AIM 2提案实验，以跟踪在哮喘的急性和慢性阶段，通过TGF¿1信号传导在肺中募集的MSC的谱系承诺/分化。我们已经建立了一个诱导的MSC谱系跟踪小鼠模型（Nestin-Creert2; Rosa26-EGFP），我们将使用该模型来跟踪急性和慢性过敏原诱导的哮喘模型的招募MSC的谱系承诺。这将提供有关TGF- - 1信号传导和MSC在过敏性哮喘中的作用的新见解，并为新型疗法提供了机会。