Lung regeneration and the stem cell niche

肺再生和干细胞生态位

• 批准号: 7837494
• 负责人: Stijn Piet Johan De Langhe
• 金额: $ 20.37万
• 依托单位: NATIONAL JEWISH HEALTH
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7837494
• 关键词: Adult; Alveolar Duct; Basal Cell; Bromodeoxyuridine; Cell Lineage; Cells; Chronic lung disease; Data; Development; Distal; Embryo; Epithelial; Epithelial Cells; Goals; Growth Factor; Health; Hyperplasia; Injury; Lung; Maintenance; Malignant neoplasm of lung; Mesenchyme; Modality; Molecular; Monitor; Naphthalene; Naphthalenes; Natural regeneration; Pathway interactions; Phenotype; Predisposing Factor; Process; Publishing; Role; Signal Transduction; Smooth Muscle Myocytes; Stem cells; Therapeutic; WNT Signaling Pathway; airway epithelium; bronchial epithelium; epithelial to mesenchymal transition; fibroblast growth factor 10; improved; lung development; paracrine; precursor cell; progenitor; public health relevance; repaired; response; stem cell niche

DESCRIPTION (provided by applicant): During lung development FGF10 (Fibroblast growth factor 10) is secreted by the parabronchial smooth muscle cell (PSMC) progenitors in the distal mesenchyme and activates the canonical WNT signaling pathway in the distally located epithelial progenitors to maintain them and sustain their proliferation. Our recently published results indicate that in the embryonic lung, (-catenin signaling in the PSMC progenitors is also essential for their maintenance and proliferation. The goal in this proposal is to determine if this pathway can be reactivated in adults to promote reepithelialization of damaged airway epithelium. Our preliminary findings illustrate reactivation of this embryonic signaling cascade in the mature PSMCs shortly after naphthalene injury. After naphthalene injury some of the PSMCs show activated TOPGAL activity, as a readout for activated (-catenin signaling, undergo massive proliferation as monitored by BrdU incorporation and reexpress Fgf10. Our data suggest that this paracrine FGF10 signaling by the PSMCs is critical for epithelial repair after naphthalene injury possibly by activating the latent bronchioalveolar stem cells (BASCs) at the Bronchio-alveolar duct junctions (BADJs). Our preliminary data also indicate an additional cellular contribution by the PSMCs in epithelial repair after naphthalene injury. We show that mature PSMCs can dedifferentiate and undergo Mesenchymal to Epithelial Transition (MET) to contribute directly to the epithelial repair process. This suggests a dual major role for the PSMCs in epithelial repair after naphthalene injury. Hypothesis: Dedifferentiation of parabronchial smooth muscle cells and/or their recapitulation of a progenitor like phenotype, is critical for epithelial regeneration after injury. Aim 1: To determine the differentiation status of the surrounding (non-epithelial) "niche" cells after naphthalene injury and their potential paracrine role in epithelial regeneration after naphthalene injury. Aim 2: To determine the differentiation status and cellular contribution of the PSMCs to epithelial repair after naphthalene injury. PUBLIC HEALTH RELEVANCE: Remodeling of the airway epithelium is a common pathological feature in chronic lung disease and a predisposing factor in the development of lung cancer. Accordingly, understanding cellular and molecular mechanisms of epithelial maintenance and repair are fundamental to the development of improved therapeutic modalities for the treatment of chronic lung disease. We hypothesize that after epithelial injury, the surrounding non-epithelial cells get reprogrammed to contribute, directly and indirectly be secreting growth factors, to the epithelial repair.

描述（由申请人提供）：在肺发育期间FGF10（成纤维细胞生长因子10）由远端间质的副管平滑肌细胞（PSMC）祖细胞分泌维持他们的扩散。我们最近发表的结果表明，在胚胎肺中，（PSMC祖细胞中的-Catenin信号传导对于它们的维持和增殖也至关重要。该提案中的目标是确定该途径是否可以在成年人中重新激活以促进受损气道的重新上皮化。上皮。我们的初步发现说明了萘损伤后不久成熟的PSMC中这种胚胎信号的重新激活。并重新表达FGF10。表明萘损伤后PSMC在上皮修复中提出了额外的细胞贡献。我们表明，成熟的PSMC可以推断并经历间质上皮转变（MET），以直接促进上皮修复过程。这表明萘损伤后，PSMC在上皮修复中具有双重作用。假设：副教平滑肌细胞和/或它们对表型等祖细胞的概括对损伤后上皮再生至关重要。目标1：确定萘损伤后周围（非上皮）“小裂”细胞的分化状态及其在萘损伤后潜在的旁分泌作用。目标2：确定萘损伤后PSMC对上皮修复的分化状态和细胞贡献。公共卫生相关性：气道上皮的重塑是慢性肺部疾病的常见病理特征，是肺癌发展的诱人因素。因此，了解上皮维持和修复的细胞和分子机制对于改善治疗治疗慢性肺部疾病的治疗方法的发展至关重要。我们假设在上皮损伤后，周围的非上皮细胞被重新编程，以直接和间接地分泌生长因子，以促进上皮修复。