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Dev Cell ; 56(11): 1646-1660.e5, 2021 06 07.
Article in English | MEDLINE | ID: covidwho-1233404


Mucus-secreting goblet cells are the dominant cell type in pulmonary diseases, e.g., asthma and cystic fibrosis (CF), leading to pathologic mucus metaplasia and airway obstruction. Cytokines including IL-13 are the major players in the transdifferentiation of club cells into goblet cells. Unexpectedly, we have uncovered a previously undescribed pathway promoting mucous metaplasia that involves VEGFa and its receptor KDR. Single-cell RNA sequencing analysis coupled with genetic mouse modeling demonstrates that loss of epithelial VEGFa, KDR, or MEK/ERK kinase promotes excessive club-to-goblet transdifferentiation during development and regeneration. Sox9 is required for goblet cell differentiation following Kdr inhibition in both mouse and human club cells. Significantly, airway mucous metaplasia in asthmatic and CF patients is also associated with reduced KDR signaling and increased SOX9 expression. Together, these findings reveal an unexpected role for VEGFa/KDR signaling in the defense against mucous metaplasia, offering a potential therapeutic target for this common airway pathology.

Airway Obstruction/genetics , Metaplasia/genetics , SOX9 Transcription Factor/genetics , Vascular Endothelial Growth Factor A/genetics , Vascular Endothelial Growth Factor Receptor-2/genetics , Airway Obstruction/metabolism , Airway Obstruction/pathology , Animals , Cell Transdifferentiation/genetics , Disease Models, Animal , Gene Expression Regulation/genetics , Goblet Cells/metabolism , Goblet Cells/pathology , Humans , Interleukin-13/genetics , MAP Kinase Signaling System/genetics , Metaplasia/pathology , Mice , Mucus/metabolism , Single-Cell Analysis
Int J Legal Med ; 134(4): 1285-1290, 2020 Jul.
Article in English | MEDLINE | ID: covidwho-544132


Forensic investigations generally contain extensive morphological examinations to accurately diagnose the cause of death. Thus, the appearance of a new disease often creates emerging challenges in morphological examinations due to the lack of available data from autopsy- or biopsy-based research. Since late December 2019, an outbreak of a novel seventh coronavirus disease has been reported in China caused by "severe acute respiratory syndrome coronavirus 2" (SARS-CoV-2). On March 11, 2020, the new clinical condition COVID-19 (Corona-Virus-Disease-19) was declared a pandemic by the World Health Organization (WHO). Patients with COVID-19 mainly have a mild disease course, but severe disease onset might result in death due to proceeded lung injury with massive alveolar damage and progressive respiratory failure. However, the detailed mechanisms that cause organ injury still remain unclear. We investigated the morphological findings of a COVID-19 patient who died during self-isolation. Pathologic examination revealed massive bilateral alveolar damage, indicating early-phase "acute respiratory distress syndrome" (ARDS). This case emphasizes the possibility of a rapid severe disease onset in previously mild clinical condition and highlights the necessity of a complete autopsy to gain a better understanding of the pathophysiological changes in SARS-CoV-2 infections.

Betacoronavirus , Coronavirus Infections/pathology , Lung/pathology , Pneumonia, Viral/pathology , Alveolar Epithelial Cells/pathology , Autopsy , COVID-19 , Cough/virology , Diabetes Mellitus, Type 2 , Fever/virology , Fibrin/metabolism , Fibrosis/pathology , Humans , Hyperplasia/pathology , Hypertension , Lung/metabolism , Lymphocytes/pathology , Macrophages/pathology , Male , Megakaryocytes/pathology , Metaplasia/pathology , Middle Aged , Neutrophils/pathology , Pandemics , Quarantine , SARS-CoV-2 , Tachycardia/virology , Thrombosis/pathology