Epithelial Stem/Progenitor Cells in Repair of the Injured Lung

上皮干细胞/祖细胞修复受损肺

基本信息

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
项目类别：
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

项目摘要

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（由申请人提供）：成人肺上皮通常会遭受环境毒素和内在肺部疾病的损伤，目前的肺范例认为上皮修复可归因于表达成熟谱系标记的细胞，相反，使用谱系追踪、单细胞。最近，通过 RNA 测序和原位移植，在正常小鼠肺中定义了先前未表征的谱系阴性上皮干细胞/祖细胞 (LNEP) 群体流感或博莱霉素损伤后，静止的 LNEP 会激活重塑程序，通过该程序，它们会增殖并广泛迁移到几乎没有成熟谱系的严重损伤区域，随后它们会分化为适当的位置，或直接分化为 II 型细胞。基底细胞样转录程序激活后的球杆细胞、纤毛细胞或 II 型细胞。该项目的中心假设是未分化的上皮细胞。干细胞/祖细胞（LNEP）存在于小鼠和人类肺实质中，响应缺氧而激活，并扩展到实质中。然而，它们随后的分化严重依赖于支持肺再生或促进异常、失败的微环境输入。导致肺部无功能的重组，即微蜂窝状。该应用的主要目标是定义损伤后介导 LNEP 激活的信号，以及决定其成功或失败的因素。修复期间无法再生正常肺泡衬里细胞的另一个关键目标是定义人类 LNEP 的等效物，并测试人类 LNEP 在间质性肺疾病中激活并促进肺重塑的想法，了解 LNEP 命运的决定因素。重大损伤应该为肺再生以及患病、纤维化肺发展的病理过程提供新的见解。