Single-cell transcriptomics of a dynamic cell behavior in murine airways
- LASE Innovation Inc, United States
- Broad Institute, United States
- Harvard Medical School, United States
- Massachusetts General Hospital, United States
Abstract
Despite advances in high-dimensional cellular analysis, the molecular profiling of dynamic behaviors of cells in their native environment remains a major challenge. We present a method that allows us to couple physiological behaviors of cells in an intact murine tissue to deep molecular profiling of individual cells. This method enabled us to establish a novel molecular signature for a striking migratory cellular behavior following injury in murine airways.
Data availability
Sequencing data have been deposited in GEO under accession code GSE193954.
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Single-cell transcriptomics of dynamic cell behaviorsNCBI Gene Expression Omnibus, GSE193954.
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A single cell atlas of the airway epithelium reveals the CFTR-rich pulmonary ionocyteNCBI Gene Expression Omnibus, GSE102580.
Article and author information
Author details
Funding
National Heart, Lung, and Blood Institute (5P01HL120839)
- Seok-Hyun Yun
National Heart, Lung, and Blood Institute (5F32HL154638)
- Daniel T Montoro
National Institute of Biomedical Imaging and Bioengineering (P41EB015903)
- Seok-Hyun Yun
National Institute of Biomedical Imaging and Bioengineering (P41EB015903)
- Seok-Hyun Yun
National Cancer Institute (R01CA192878)
- Seok-Hyun Yun
National Heart, Lung, and Blood Institute (K08HL124298)
- Vladimir Vinarsky
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: Mice were maintained in an Association for Assessment and Accreditation of Laboratory Animal Care-accredited animal facility at the Massachusetts General Hospital, and procedures were performed with Institutional Animal Care and Use Committee (IACUC)-approved protocol 2009N000119.
Copyright
© 2023, Kwok et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Single-cell transcriptomics of a dynamic cell behavior in murine airways
eLife 12:e76645.
https://doi.org/10.7554/eLife.76645
Further reading
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- Developmental Biology
Premature infants with bronchopulmonary dysplasia (BPD) have impaired alveolar gas exchange due to alveolar simplification and dysmorphic pulmonary vasculature. Advances in clinical care have improved survival for infants with BPD, but the overall incidence of BPD remains unchanged because we lack specific therapies to prevent this disease. Recent work has suggested a role for increased transforming growth factor-beta (TGFβ) signaling and myofibroblast populations in BPD pathogenesis, but the functional significance of each remains unclear. Here, we utilize multiple murine models of alveolar simplification and comparative single-cell RNA sequencing to identify shared mechanisms that could contribute to BPD pathogenesis. Single-cell RNA sequencing reveals a profound loss of myofibroblasts in two models of BPD and identifies gene expression signatures of increased TGFβ signaling, cell cycle arrest, and impaired proliferation in myofibroblasts. Using pharmacologic and genetic approaches, we find no evidence that increased TGFβ signaling in the lung mesenchyme contributes to alveolar simplification. In contrast, this is likely a failed compensatory response, since none of our approaches to inhibit TGFβ signaling protect mice from alveolar simplification due to hyperoxia while several make simplification worse. In contrast, we find that impaired myofibroblast proliferation is a central feature in several murine models of BPD, and we show that inhibiting myofibroblast proliferation is sufficient to cause pathologic alveolar simplification. Our results underscore the importance of impaired myofibroblast proliferation as a central feature of alveolar simplification and suggest that efforts to reverse this process could have therapeutic value in BPD.
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- Developmental Biology
Cells called alveolar myofibroblasts, which have a central role in the development of the lung after birth, receive an orchestrated input from a range of different signaling pathways.
