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Principal Investigator: Jason Spence
Organization: UNIVERSITY OF MICHIGAN AT ANN ARBOR
Fiscal Year: 2024
Award: $570,518
Funding agency: National Heart Lung and Blood Institute
ABSTRACT
During a recent single cell RNA sequencing analysis of the developing human lung, we identified a cell
population characterized by a unique gene expression profile that has not previously been reported in the
human or mouse lung. These cells express SCGB3A2/SFTPB/CFTR, but lack markers for other well
characterized cell types such as club cells (SCGB1A1) or ionocytes (FOXI1). We refer to these as Fetal Airway
Secretory (FAS) cells given the expression of several secretory genes within the transcriptional signature.
Since nothing is known about FAS cells, and there is no analogous population in the murine lung, the
overarching goal of this proposal is to both describe these cells in detail, to interrogate their differentiation
potential, and to determine how these cells are regulated. By using an in vitro model of the developing human
lung epithelium called human Bud Tip Progenitor (BTP)-organoids, preliminary data shows that BTP-organoids
can give rise to both TP63+ progenitors and FAS cells during airway differentiation, and that this differentiation
can be modulated by TGFb/BMP/SMAD signaling. Single cell barcode-based lineage tracing during the
transition from BTP-to-airway suggest that clones of FAS cells or basal cells give rise to distinct subsets of
airway cells, with FAS cells giving rise to pulmonary neuroendocrine cells (PNECs) and a subset of C6+
multiciliated (MC) cells, while TP63+ progenitor cells give rise to secretory cells and MUC16+ MC cells. Based
on this data, we will test the overarching hypothesis that FAS cells differentiate distinct airway progenitor cell
that give rise to a subset of airway cell types. Given the novelty of this cell type, and the unique tools that we
have developed to assess the differentiating human epithelium in vitro, understanding this cell population will
provide foundational descriptive and mechanistic insights into human lung biology.
Terms: <ACSL1><ACSL1 Gene><ASCL1><ASCL1 gene><ASCL1 protein><ASH1><Achaete-Scute Complex Homolog-Like 1 Protein><Achaete-Scute Complex-Like 1 Protein><Achaete-Scute Homolog 1 Protein><Active Follow-up><Atlases><Bar Codes><Basal Cell><Biology><Body Tissues><CFTR><CFTR Protein><Cell Body><Cell Communication and Signaling><Cell Differentiation><Cell Differentiation process><Cell Lineage><Cell Signaling><Cell surface><Cells><Conceptions><Cystic Fibrosis Transmembrane Conductance Regulator><Data><Epithelial Cells><Epithelium><Expression Signature><Gene Expression Profile><Gene Modified><Genes><Goals><HASH1><HASH1 protein><Human><In Vitro><Intracellular Communication and Signaling><JV18><JV18-1><Lung><Lung Respiratory System><MADH2><MADH2 gene><MADR2><MASH 1 protein><MASH1><MASH1 protein><Mammalian Achaete-Scute Homolog 1><Mediating><Methods><Mice><Mice Mammals><Modeling><Modern Man><Murine><Mus><Neuroendocrine Cell><Organoids><Phase><Population><Progenitor Cells><Publishing><Reporting><SMAD2><Secretory Cell><Signal Transduction><Signal Transduction Systems><Signaling><System><Testing><Time Series Analysis><Tissues><active followup><barcode><biological signal transduction><cell type><cellular differentiation><cystic fibrosis transmembrane regulator><experiment><experimental research><experimental study><experiments><fetal><follow up><follow-up><followed up><followup><gene expression pattern><gene expression signature><gene modification><gene signatures><genetic signature><genetically modified><in vitro Model><inhibitor><insight><novel><pharmacologic><progenitor><pulmonary><scRNA-seq><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell transcriptomic profiling><single-cell RNA sequencing><stem cells><tool><transcriptional profile><transcriptional signature>