Publications by authors named "Katherine B McCauley"

Receptor-mediated signaling plays a central role in tissue regeneration, and it is dysregulated in disease. Here, we build a signaling-response map for a model regenerative human tissue: the airway epithelium. We analyzed the effect of 17 receptor-mediated signaling pathways on organotypic cultures to determine changes in abundance and phenotype of epithelial cell types.

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Receptor-mediated signaling plays a central role in tissue regeneration, and it is dysregulated in disease. Here, we build a signaling-response map for a model regenerative human tissue: the airway epithelium. We analyzed the effect of 17 receptor-mediated signaling pathways on organotypic cultures to determine changes in abundance and phenotype of all epithelial cell types.

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The human lung differs substantially from its mouse counterpart, resulting in a distinct distal airway architecture affected by disease pathology in chronic obstructive pulmonary disease. In humans, the distal branches of the airway interweave with the alveolar gas-exchange niche, forming an anatomical structure known as the respiratory bronchioles. Owing to the lack of a counterpart in mouse, the cellular and molecular mechanisms that govern respiratory bronchioles in the human lung remain uncharacterized.

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New protocols to efficiently generate functional airway epithelial organoids from human pluripotent stem cells (PSCs) would represent a major advance towards effective disease modeling, drug screening and cell based therapies for lung disorders. This unit describes an approach using stage-specific signaling pathway manipulation to differentiate cells to proximal airway epithelium via key developmental intermediates. Cells are directed via definitive endoderm (DE) to anterior foregut, and then specified to NKX2-1+ lung epithelial progenitors.

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Article Synopsis
  • Scientists have created new mouse and human stem cell lines with special reporters that help track and study airway secretory cells generated from pluripotent stem cells (PSCs).
  • These engineered cells show a tendency to adopt characteristics of both airway and alveolar cell types, indicating a level of flexibility in their development.
  • By inhibiting Wnt signaling, researchers can reduce this plasticity, providing valuable insights for better directing the differentiation of lung cells and creating a model for human airway development.
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Article Synopsis
  • Researchers successfully created alveolar epithelial type 2 cells (AEC2s) from human pluripotent stem cells (PSCs), a crucial step for studying lung development and diseases.* -
  • They tracked the development of these cells using fluorescent markers and found that the cells could form structures called "alveolospheres" independently in 3D cultures.* -
  • The study also demonstrated gene correction in PSCs from patients with a surfactant mutation, showing potential for modeling diseases and regenerating lung tissue in the future.*
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Article Synopsis
  • Researchers have discovered specific signaling pathways needed to differentiate pluripotent stem cells into either lung or thyroid epithelial cells, which has been unclear in past studies.
  • They identified Wnt+BMP signaling as essential for lung specification, while BMP+FGF signaling is necessary for thyroid cells, highlighting a difference in their development.
  • This refined understanding can help create distinct progenitor cells for advanced studies and potential therapies, as these pathways remain consistently recognized across both mice and humans.
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It has been postulated that during human fetal development, all cells of the lung epithelium derive from embryonic, endodermal, NK2 homeobox 1-expressing (NKX2-1+) precursor cells. However, this hypothesis has not been formally tested owing to an inability to purify or track these progenitors for detailed characterization. Here we have engineered and developmentally differentiated NKX2-1GFP reporter pluripotent stem cells (PSCs) in vitro to generate and isolate human primordial lung progenitors that express NKX2-1 but are initially devoid of differentiated lung lineage markers.

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Effective derivation of functional airway organoids from induced pluripotent stem cells (iPSCs) would provide valuable models of lung disease and facilitate precision therapies for airway disorders such as cystic fibrosis. However, limited understanding of human airway patterning has made this goal challenging. Here, we show that cyclical modulation of the canonical Wnt signaling pathway enables rapid directed differentiation of human iPSCs via an NKX2-1 progenitor intermediate into functional proximal airway organoids.

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