Human alveolar Type 2 epithelium transdifferentiates into metaplastic KRT5+ basal cells during alveolar repair

• DOI: 10.1101/2020.06.06.136713
• Publication Date: 2020-06-07T09:15:11Z
• Authors: Jaymin J. Kathiriya; Chaoqun Wang; Alexis Brumwell; Monica Cassandras; Claude Le Saux; Paul Wolters; Michael Matthay; Harold A Chapman; Tien Peng
• Keywords: Transdifferentiation; Basal (medicine)

SUMMARY Understanding differential lineage potential of orthologous stem cells across species can shed light on human disease. Here, utilizing 3D organoids, single cell RNAseq, and xenotransplants, we demonstrate that alveolar type 2 (hAEC2s), unlike murine AEC2s, are multipotent able to transdifferentiate into KRT5+ basal when co-cultured with primary fibroblasts in organoids. Trajectory analyses immunophenotyping epithelial progenitors idiopathic pulmonary fibrosis (IPF) indicate hAEC2s metaplastic through alveolar-basal intermediate (ABI) also identify hAEC2-derived Modulating hAEC2-intrinsic niche factors dysregulated IPF attenuate transdifferentiation preserve hAEC2 identity. Finally, transplanted fibrotic immune-deficient lungs engraft as either or differentiated cells. Our study indicates hAEC2s-loss expansion causally connected, which would not have been revealed AEC2s a model. Highlights Human accompanied by adult lung mesenchyme organoid culture. Alterations modify transdifferentiation. mice Transcriptional trajectory analysis suggests gives rise via