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Characterization of a New Epithelial Cell in the Developing Human Lung

发育中的人肺中新上皮细胞的表征

基本信息

批准号：
10514524
负责人：
Ansley Corinne Semack Conchola
金额：
$ 4.12万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-01 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10514524
关键词：
Antibodies Archives Bar Codes Blocking Antibodies Bronchi Cell Differentiation process Cell Maintenance Cell Surface Proteins Cell physiology Cell surface Cells Complex Computer software Cues Cystic Fibrosis Transmembrane Conductance Regulator Data Decision Making Development Distal Dominant-Negative Mutation ES01 Epithelial Epithelial Cells Fetal Lung Fetal Tissues Fluorescence-Activated Cell Sorting Gene Expression Gene Expression Profile Goals Human In Situ Light Lung Methods Modeling Morphogenesis Mus Organoids Pharmacology Population Process Publishing Pulmonary alveolar structure Reagent Regulation Role Route Secretory Cell Signal Transduction Stains Structure of parenchyma of lung Testing Time Tissue Banks Trachea airway epithelium base cell type cohort data repository experimental study fetal gain of function human embryonic stem cell in vitro Model in vivo induced pluripotent stem cell inhibitor loss of function lung development novel progenitor single-cell RNA sequencing spatiotemporal

项目摘要

PROJECT ABSTRACT The lung buds undergo a process known as branching morphogenesis, which establishes the complex, arborized network of the lung1–7. During branching, a specialized population of lung progenitors at the tips of the branches, bud tip progenitors (BTPs), give rise to all epithelial cell types of the lung including cells of the proximal airway (trachea, bronchi) and cells of the distal lung (alveoli)1,8–16. We recently performed single-cell RNA sequencing (scRNAseq) on the human fetal lung from 10 to 21 weeks gestation16, and identified a novel epithelial cell population characterized by a unique gene expression profile: SCGB3A2HI/SFTPB HI/CFTRHI which we refer to as Fetal Airway Secretory (FAS) cells. We have shown that human BTPs grown in culture can give rise to FAS cells, and they have been verified in the small airways in situ. My preliminary data suggest that FAS cells are transient, dwindling in number across development. Further, our data suggests that FAS cells are uniquely human, and do not exist in mice. Since nothing is known about this newly identified population, the goal of this proposal is to interrogate the function, differentiation potential, and regulation of FAS cells. My preliminary data suggests that: (a) FAS cells may be a developmental precursor state that exists while BTPs are en route to becoming proximal airway and (b) FAS cell development is regulated by NOTCH signaling, a critical regulator of cell fate decision making in the developing lung17,18. Based on my preliminary data, I hypothesize that FAS cells are a transitional progenitor population that give rise to all airway cell types and NOTCH signaling regulates the transition from BTP-to-FAS to committed airway cell types. Using a novel cell barcoding lineage tracing approach in a human lung organoid model, I aim to 1) test the function of FAS cells, specifically if they differentiate into proximal airway cells. I also aim to 2) investigate the role of NOTCH signaling in FAS cells using gain-of-function and loss-of-function lentiviral constructs, NOTCH blocking antibodies, and pharmacologic inhibitors that activate or inhibit NOTCH signaling in an organoid model.

项目摘要