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Review 2: "Progenitor identification and SARS-CoV-2 infection in long-term human distal lung organoid cultures"

This study offers a chemically-defined human lung organoid culture system and employs this model to identify club cells as a novel target in SARS-CoV-2 infection. The findings reported are reliable for informing future COVID-19 research.

Published onAug 30, 2020
Review 2: "Progenitor identification and SARS-CoV-2 infection in long-term human distal lung organoid cultures"
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Progenitor identification and SARS-CoV-2 infection in long-term human distal lung organoid cultures
Progenitor identification and SARS-CoV-2 infection in long-term human distal lung organoid cultures
Description

Abstract The hippocampus has been linked to memory encoding and spatial navigation, while the prefrontal cortex is associated with cognitive functions such as decision-making. These regions are hypothesized to communicate in tasks that demand both spatial navigation and decision-making processes. However, the electrophysiological signatures underlying this communication remain to be better elucidated. To investigate the dynamics of the hippocampal-prefrontal interactions, we have analyzed their local field potentials and spiking activity recorded from rats performing an odor-cued spatial alternation task in an 8-shaped maze. We found that the phase coherence of theta peaked around the choice point area of the maze. Moreover, Granger causality revealed a hippocampus->prefrontal cortex directionality of information flow at theta frequency, peaking at starting areas of the maze, and on the reverse direction at delta frequency, peaking near the turn onset. Additionally, the patterns of phase-amplitude cross-frequency coupling within and between the regions also showed spatial selectivity, and a new method revealed that hippocampal theta and prefrontal delta modulated not only gamma amplitude but also inter-regional gamma synchrony. Lastly, we found that the theta rhythm dynamically modulated neurons in both regions, with the highest modulation at the choice area; interestingly, prefrontal cortex neurons were more strongly modulated by the hippocampal theta rhythm than by their local field rhythm. In all, our results reveal maximum electrophysiological interactions between the hippocampus and the prefrontal cortex near the decision-making period of the spatial alternation task. These results corroborate the hypothesis that a dynamic interplay between these regions takes place during spatial decisions.

RR:C19 Evidence Scale rating by reviewer:

  • Strong. The main study claims are very well-justified by the data and analytic methods used. There is little room for doubt that the study produced has very similar results and conclusions as compared with the hypothetical ideal study. The study’s main claims should be considered conclusive and actionable without reservation.

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Review Summary: This is outstanding, well-documented work that generates new methodologies for isolation and culture of lung epithelial progenitor cells from peripheral regions of the human lung. New and highly efficient methods are carefully described to ensure reproducibility of the work. Importantly , methods for clinical isolation and expansion of basal progenitors and their differentiation in a defined medium in the absence_of feeder cells are provided. A distinct subset of  basal and alveolar progenitors was  identified, cloned, and efficiently expanded. The investigators provide detailed and appropriate cell markers and temporal changes in organoid architecture and gene expression. Of considerable interest to the field, an TNFRSF12A subset of “basal 1” cells with distinct progenitor cell properties was identified in the organoid cultures and verified in the normal human lung. Both peripheral basal progenitors and alveolar progenitors were efficiently expanded in vitro. Highly proliferative basal 1 like cells were prepared directly from human lung, bypassing the organoid culture steps. The authors used organoids to identify their susceptibility to influenza virus and SARS-Cov2 infection using a method to invert the architecture of the organoids, presenting the apical surfaces of the epithelial cells to the external medium, thereby enabling quantification of cell type-specific infection by the virus. Inverted basal derived and alveolar cell cultures were readily infected by SARS-Cov2, the cells expressing both ACE2 and TMPRSS2. Single cell RNA data, FACs, and confocal microscopy carefully documented the morphology and cell composition of the organoids and their infection by SARS-Cov2.The authors identified Club secretory cells which were selectively infected  by the virus and the lack of infection of highly differentiated ciliated cells. Methods for cell culture, organoid formation, characterization, and infection are rigorously documented ,enabling reproducibility and implementation by the field. The ability to rapidly isolate and  expand clones of  subsets of peripheral airway and alveolar epithelial cells and  organoids will support mechanistic and translational studies informing the pathogeneses of pulmonary viral infection in general, and will be useful for the study of the cell and molecular biology of SARS-Cov2 infection and for screening of antiviral therapies. 

The work will be highly appreciated by the research community in pulmonary biology, medicine, and infectious diseases and will enable translational studies relevant to the COVID-19 pandemic.

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