Plasticity of Hopx(+) type I alveolar cells to regenerate type II cells in the lung
Open accessAbstract
The plasticity of differentiated cells in adult tissues undergoing repair is an area of intense research. Pulmonary alveolar type II cells produce surfactant and function as progenitors in the adult, demonstrating both self-renewal and differentiation into gas exchanging type I cells. In vivo, type I cells are thought to be terminally differentiated and their ability to give rise to alternate lineages has not been reported. Here we show that Hopx becomes restricted to type I cells during development. However, unexpectedly, lineage-labelled Hopx+ cells both proliferate and generate type II cells during adult alveolar regrowth following partial pneumonectomy. In clonal 3D culture, single Hopx+ type I cells generate organoids composed of type I and type II cells, a process modulated by TGFβ signalling. These findings demonstrate unanticipated plasticity of type I cells and a bidirectional lineage relationship between distinct differentiated alveolar epithelial cell types in vivo and in single-cell culture. Alveoli are the lung’s functional units composed of two major epithelial cell types, type I and type II. Type II cells are adult lung stem cells, but this study shows that differentiated Type I cells can also self-renew and give rise to Type II cells, revealing a bidirectional relationship between lung epithelial cell types.
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Reprogramming of differentiated cells into progenitor-like cells is an important injury-repair paradigm independent of adult stem cells in various epithelial tissues in mammals.
“The reprogramming of differentiated cells into progenitor-like cells has recently been discovered as an important injury-repair paradigm independent of adult stem cells in a variety of epithelial tissues in mammals, 1 such as the lung, 2 intestine, 3 pancreas, 4 and liver.5,6”
From Kupffer-cell-derived IL-6 is repurposed for hepatocyte dedifferentiation via activating progenitor genes from injury-specific enhancers (2023) · cites this paper as [2]
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- Authors
- Jain, R., Barkauskas, C. E., Takeda, N., Bowie, E. J., Aghajanian, H., Wang, Q., Padmanabhan, A., Manderfield, L. J., Gupta, M., Li, D., Li, L., Trivedi, C. M., Hogan, B. L. M., & Epstein, J. A.
- Affiliations
- University of Pennsylvania (US)
- Duke University (US)
- Corresponding author
- Hogan, Brigid L. M.
- Epstein, Jonathan A.
- ORCID
- Venue
- Nature Communications
- Published
- 2015-04-13
- Volume
- 6
- Issue
- 1
- Pages
- 6727-6727
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC4396689
- OpenAlex
- W2076684565
- Cited by
- 303
- References
- 39
- Citations by year
- 2026: 12 · 2025: 16 · 2024: 24 · 2023: 35 · 2022: 32 · 2021: 38 · 2020: 30 · 2019: 29 · 2018: 26 · 2017: 30 · 2016: 22 · 2015: 8 · 2014: 1
- FWCI
- 22.70
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Nature Communications (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- University of Pennsylvania
- Cotswold Foundation
- National Institutes of Health
- Japan Society for the Promotion of Science (15K09132)
- National Heart, Lung, and Blood Institute (K08HL122521, R01HL071546, U01HL100405, U01HL110967, U01HL111018, K08HL119553, UO1HL110967, UO1HL111018, U01HL110942)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (T32HD040372)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Neonatal Respiratory Health Research
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Health Sciences › Medicine › Surgery › Transplantation: Methods and Outcomes
- Keywords
- HOPX, alveolar type I cells, alveolar type II cells, cellular plasticity, lung regeneration, alveolar epithelial cells, TGF-beta signaling, lung organoids, partial pneumonectomy, lung stem cells, lineage relationships, self-renewal, surfactants
- MeSH terms
- Animals, Cell Differentiation, Clone Cells, Crosses, Genetic, Epithelial Cells, Humans, Male, Mice, Transgenic, Pneumonectomy, Pulmonary Alveoli, Regeneration, Tamoxifen, Signal Transduction, Gene Expression, Transforming Growth Factor beta, Genes, Reporter, Homeodomain Proteins, Cell Culture Techniques, Cell Lineage, Cell Proliferation, Green Fluorescent Proteins, Mice, Cell Tracking
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