Epithelial Stem/Progenitor Cells in Repair of the Injured Lung

上皮干细胞/祖细胞修复受损肺

• 批准号: 9109038
• 负责人: Harold A Chapman
• 金额: $ 49.63万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-15 至 2020-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9109038
• 关键词: Adult; Alleles; Alveolar; Alveolus; Architecture; Area; Basal Cell; Biological Assay; Biological Markers; Bleomycin; Cell Death; Cell Differentiation process; Cell Line; Cells; Chronic; Coculture Techniques; Complex; Distal; Elements; Environment; Environmental Exposure; Epithelial; Epithelial Cells; Epithelium; Failure; Fibroblasts; Goals; Growth; HIF1A gene; Health; Homeostasis; Human; Hypoxia; Immune; Influenza; Influenza A Virus, H1N1 Subtype; Injury; Interstitial Lung Diseases; Label; Ligands; Location; Lung; Lung diseases; Mediating; Methods; Molecular; Mus; Natural regeneration; Pathologic Processes; Pathway interactions; Population; Process; Proliferating; Pulmonary Surfactant-Associated Protein C; Reporter; Role; Scleroderma; Signal Transduction; Stem cells; Structure of parenchyma of lung; Structure of thyroid parafollicular cell; Testing; Tissues; Toxic Environmental Substances; Transitional Cell; Transplantation; Type II Epithelial Receptor Cell; Undifferentiated; base; cell type; cytokine; experience; in vitro Assay; in vivo; injured; insight; laser capture microdissection; lung regeneration; lung repair; notch protein; novel; progenitor; programs; receptor; regenerative; repaired; response; restoration; stem; success; transcriptome sequencing

 DESCRIPTION (provided by applicant): The adult lung epithelium commonly endures injury from environmental toxins and intrinsic lung disease. Current paradigms in the lung posit that epithelial repair can be attributed to cells expressing mature lineage markers. In contrast, using lineage tracing, single cell RNA-sequencing, and orthotopic transplantation, a previously uncharacterized lineage-negative epithelial stem/progenitor (LNEPs) population was recently defined within the normal mouse lung parenchyma. Quiescent LNEPs activate a remodeling program after influenza or bleomycin injury by which they proliferate and migrate widely to occupy heavily injured areas nearly devoid of mature lineages, whereupon they differentiate appropriate to location. LNEPs appear capable of differentiating into type II cells directly or to club cells, ciliated cells, or type II cells following activation of a basal cell-like transcriptioal program. The central hypothesis of this project is that undifferentiated epithelial stem/progenitors (LNEPs) exist in mouse and human lung parenchyma, activate in response to hypoxia, and expand into the parenchyma. However, their subsequent differentiation is critically dependent on micro-environmental inputs that either support lung regeneration or promote an aberrant, failed re-organization resulting in non-functional lung, i.e. micro-honeycombing. The major objectives of the application are to define the signals that mediate LNEP activation after injury, and what determines their success or failure to regenerate normal alveolar lining cells during repair. Another key objective is to define the human equivalent of murine LNEPs and test the idea that human LNEPs activate and contribute to lung remodeling in the context of interstitial lung disease. Understanding the determinants of LNEP fate after major injury should provide new insights into lung regeneration and the pathological process by which diseased, fibrotic lungs develop.

 描述（由申请方提供）：成人肺上皮通常会遭受环境毒素和内源性肺病的损伤。目前肺的范例表明，上皮修复可归因于表达成熟谱系标志物的细胞。相比之下，使用谱系追踪，单细胞RNA测序和原位移植，以前未表征的谱系阴性上皮干/祖细胞（LNEPs）的人口最近被定义在正常小鼠肺实质。静止的LNEP在流感或博来霉素损伤后激活重塑程序，通过该程序它们增殖并广泛迁移以占据几乎没有成熟谱系的严重损伤区域，因此它们分化为适当的位置。LNEP似乎能够直接分化为II型细胞，或在基底细胞样转录程序激活后分化为俱乐部细胞、纤毛细胞或II型细胞。该项目的中心假设是未分化的上皮干/祖细胞（LNEPs）存在于小鼠和人肺实质中，响应于缺氧而活化，并扩展到实质中。然而，它们随后的分化严重依赖于微环境输入，微环境输入支持肺再生或促进异常的、失败的重组，导致非功能性肺，即微蜂窝。该应用程序的主要目标是定义损伤后介导LNEP激活的信号，以及在修复过程中决定其成功或失败再生正常肺泡衬里细胞的因素。另一个关键目标是定义小鼠LNEP的人类等效物，并测试人类LNEP在间质性肺病的背景下激活并促进肺重塑的想法。了解严重损伤后LNEP命运的决定因素应该为肺再生和病变纤维化肺发展的病理过程提供新的见解。