Cross-species integration of single-cell RNA-seq resolved alveolar-epithelial transitional states in idiopathic pulmonary fibrosis
| Autor: | Kevin Y Huang, Enrico Petretto |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Pulmonary and Respiratory Medicine Pathology medicine.medical_specialty Physiology Alveolar Epithelium Cell RNA-Seq Respiratory Mucosa Biology Lung injury Transcriptome Mice 03 medical and health sciences Idiopathic pulmonary fibrosis 0302 clinical medicine Species Specificity Physiology (medical) medicine Animals Humans Mice Knockout Lung Cell Biology medicine.disease Idiopathic Pulmonary Fibrosis Disease Models Animal 030104 developmental biology medicine.anatomical_structure Gene Expression Regulation Alveolar Epithelial Cells 030220 oncology & carcinogenesis Transitional Cell Single-Cell Analysis |
| Zdroj: | American Journal of Physiology-Lung Cellular and Molecular Physiology. 321:L491-L506 |
| ISSN: | 1522-1504 1040-0605 |
| Popis: | Single-cell transcriptomics analyses of the fibrotic lung uncovered two cell states critical to lung injury recovery in the alveolar epithelium—a reparative transitional cell state in the mouse and a disease-specific cell state ( KRT5−/ KRT17+) in human idiopathic pulmonary fibrosis (IPF). The murine transitional cell state lies between the differentiation from type 2 (AT2) to type 1 pneumocyte (AT1), and the human KRT5−/ KRT17+ cell state may arise from the dysregulation of this differentiation process. We review major findings of single-cell transcriptomics analyses of the fibrotic lung and reanalyzed data from seven single-cell RNA sequencing studies of human and murine models of IPF, focusing on the alveolar epithelium. Our comparative and cross-species single-cell transcriptomics analyses allowed us to further delineate the differentiation trajectories from AT2 to AT1 and AT2 to the KRT5−/ KRT17+ cell state. We observed AT1 cells in human IPF retain the transcriptional signature of the murine transitional cell state. Using pseudotime analysis, we recapitulated the differentiation trajectories from AT2 to AT1 and from AT2 to KRT5−/ KRT17+ cell state in multiple human IPF studies. We further delineated transcriptional programs underlying cell-state transitions and determined the molecular phenotypes at terminal differentiation. We hypothesize that in addition to the reactivation of developmental programs ( SOX4, SOX9), senescence ( TP63, SOX4) and the Notch pathway ( HES1) are predicted to steer intermediate progenitors to the KRT5−/ KRT17+ cell state. Our analyses suggest that activation of SMAD3 later in the differentiation process may explain the fibrotic molecular phenotype typical of KRT5−/ KRT17+ cells. |
| Databáze: | OpenAIRE |
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