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Type 2 alveolar cells are stem cells in adult lung
Open accessAbstract
Gas exchange in the lung occurs within alveoli, air-filled sacs composed of type 2 and type 1 epithelial cells (AEC2s and AEC1s), capillaries, and various resident mesenchymal cells. Here, we use a combination of in vivo clonal lineage analysis, different injury/repair systems, and in vitro culture of purified cell populations to obtain new information about the contribution of AEC2s to alveolar maintenance and repair. Genetic lineage-tracing experiments showed that surfactant protein C-positive (SFTPC-positive) AEC2s self renew and differentiate over about a year, consistent with the population containing long-term alveolar stem cells. Moreover, if many AEC2s were specifically ablated, high-resolution imaging of intact lungs showed that individual survivors undergo rapid clonal expansion and daughter cell dispersal. Individual lineage-labeled AEC2s placed into 3D culture gave rise to self-renewing "alveolospheres," which contained both AEC2s and cells expressing multiple AEC1 markers, including HOPX, a new marker for AEC1s. Growth and differentiation of the alveolospheres occurred most readily when cocultured with primary PDGFRα⁺ lung stromal cells. This population included lipofibroblasts that normally reside close to AEC2s and may therefore contribute to a stem cell niche in the murine lung. Results suggest that a similar dynamic exists between AEC2s and mesenchymal cells in the human lung.
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“or require the presence of a mesenchymal feeder layer (Barkauskas et al., 2013)”
From Pulmonary fibrosis: Emerging diagnostic and therapeutic strategies (2023) · cites this paper as Barkauskas et al., 2013
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“and can differentiate into alveolar epithelial type 1 (AEC1) cells.”
From Pulmonary fibrosis: Emerging diagnostic and therapeutic strategies (2023) · cites this paper as Barkauskas et al., 2013
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“…of 16 EMBO Molecular Medicine e10233 | 2019 ª 2019 The Authors In addition to DASCs, many other distinct populations of adult lung stem/progenitor cells have been reported to exert regenerative functions under different circumstances (Barkauskas et al, 2013; Leeman et al, 2014; Nabhan et al, 2018).”
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BackgroundImpaired Alveolar Re-Epithelialization in Pulmonary Emphysema
Lin, C.-R., Bahmed, K., & Kośmider, B. (2022) · Cells · doi:10.3390/cells11132055 · Cited by 39
“This was determined by single-cell sequencing, lineage-tracing studies, various lung injury models, and 3D organoid culture in mice [3,5,10,16].”
BackgroundMethodInfluentialLung Organoids—The Ultimate Tool to Dissect Pulmonary Diseases?
Bosáková, V., Zuani, M. D., Sládková, L., Garlíková, Z., Jose, S. S., Zelante, T., Kohoutková, M. H., & Frič, J. (2022) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2022.899368 · Cited by 35
Club cells employ regeneration mechanisms during lung tumorigenesis
Chen, Y., Tóth, R., Chocarro, S., Weichenhan, D., Hey, J., Lutsik, P., Sawall, S., Stathopoulos, G. T., Plass, C., & Sotillo, R. (2022) · Nature Communications · doi:10.1038/s41467-022-32052-2 · Cited by 36
Pharmaceutical applications of lectins
de Juan, L. L., García-Recio, V., López, P. J., Juan, T. G., Córdoba-Díaz, M., & Córdoba-Díaz, D. (2017) · Journal of Drug Delivery Science and Technology · doi:10.1016/j.jddst.2017.05.018 · Cited by 35
New Insights into the Alveolar Epithelium as a Driver of Acute Respiratory Distress Syndrome
Zuttion, M. S. S. R., Moore, S. K., Chen, P., Beppu, A., & Hook, J. L. (2022) · Biomolecules · doi:10.3390/biom12091273 · Cited by 37
“[50,115,135], recent data show successful alveolar epithelial repair and regeneration may”
BackgroundDisruption of proteostasis causes IRE1 mediated reprogramming of alveolar epithelial cells
Katzen, J. B., Rodríguez, L. R., Tomer, Y., Babu, A., Zhao, M., Murthy, A., Carson, P., Barrett, M., Basil, M. C., Carl, J., et al. (2022) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2123187119 · Cited by 35
“The alveolar epithelial type 2 cell (AEC2) plays a critical role in homeostasis of the distal adult lung, producing pulmonary surfactant to reduce alveolar surface tension and acting as a critical progenitor cell following injury (1, 2).”
BackgroundInterrelationship between COVID-19 and Coagulopathy: Pathophysiological and Clinical Evidence
Ragnoli, B., Re, B. D., Galantino, A., Kette, S., Salotti, A., & Malerba, M. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24108945 · Cited by 38
“It was observed in rare cases that immune thrombotic thrombocy-Int topenia (VITT) syndrome was induced by the vaccine, particularly the ChAdOx1 nCoV-19 vaccine.”
BackgroundAdult Animal Stem Cell-Derived Organoids in Biomedical Research and the One Health Paradigm
Gabriel, V., Zdyrski, C., Sahoo, D. K., Ralston, A., Wickham, H., Bourgois‐Mochel, A., Ahmed, B. H., Merodio, M. M., Paukner, K., Piñeyro, P. E., et al. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25020701 · Cited by 35
“The list of described murine organoids includes the proximal airways [86], stomach [87], pancreas [88], liver [89], distal airways [90], tongue [91], esophagus [92], prostate [71], salivary gland [93], mammary gland [94], fallopian tube [95], thyroid gland [96], urinary bladder [97], epididymis…”
BackgroundEpithelial stem cells and niches in lung alveolar regeneration and diseases
Zhang, J., & Liu, Y. (2024) · Chinese Medical Journal - Pulmonary and Critical Care Medicine · doi:10.1016/j.pccm.2023.10.007 · Cited by 35
“14 , 87 Recent technological advancements such as lineage tracing and scRNA-seq have revealed significant heterogeneity among fibroblasts.”
BackgroundInfluentialFlodby, P., Li, C., Liu, Y., Wang, H., Rieger, M. E., Minoo, P., Crandall, E. D., Ann, D. K., Borok, Z., & Zhou, B. (2017) · Scientific Reports · doi:10.1038/s41598-017-03152-7 · Cited by 34
Shah, T. G., Qin, S., Vashi, M., Predescu, D. N., Jeganathan, N., Bardita, C., Ganesh, B. B., DiBartolo, S., Fogg, L., BALK, R. A., et al. (2018) · Clinical and Translational Medicine · doi:10.1186/s40169-018-0197-2 · Cited by 34
“4 days in ICU; these EVARDS show no Runx1p66, Table 2, raising the possibility that the circulatory EVARDSRunx1p66 might be needed only when the endogenous lung MSCs [36, 37] and thus, the ability of lung tissue to repair, a hallmark of the normal course of recovery from ALI in some patients [38], are not sufficient.”
BackgroundBridges, J. P., Sudha, P., Lipps, D., Wagner, A. J., Guo, M., Du, Y., Brown, K. R., Filuta, A. L., Kitzmiller, J. A., Stockman, C. A., et al. (2020) · American Journal of Physiology-Lung Cellular and Molecular Physiology · doi:10.1152/ajplung.00459.2019 · Cited by 34
Gokey, J. J., Snowball, J. M., Green, J., Waltamath, M., Spinney, J. J., Black, K. E., Hariri, L. P., Xu, Y. J., & Perl, A. T. (2021) · Thorax · doi:10.1136/thoraxjnl-2020-214986 · Cited by 34
FGF10 and Lipofibroblasts in Lung Homeostasis and Disease: Insights Gained From the Adipocytes
Lv, Y., Dhlamini, Q., Chen, C., Li, X., Bellusci, S., & Zhang, J. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.645400 · Cited by 36
Martin, T. R., Zemans, R. L., Ware, L. B., Schmidt, E. P., Riches, D. W. H., Bastarache, L. A., Calfee, C. S., Desai, T., Herold, S., Hough, C. L., et al. (2022) · American Journal of Respiratory Cell and Molecular Biology · doi:10.1165/rcmb.2022-0089ws · Cited by 38
Immunometabolism changes in fibrosis: from mechanisms to therapeutic strategies
Feng, L., Chen, X., Huang, Y., Zhang, X., Zheng, S., & Xie, N. (2023) · Frontiers in Pharmacology · doi:10.3389/fphar.2023.1243675 · Cited by 35
“Alveolar type 2 cells have the most active lipid metabolism among lung epithelial cells, rendering them frequently prone to injury (Barkauskas et al., 2013).”
BackgroundCEBPA restricts alveolar type 2 cell plasticity during development and injury-repair
Hassan, D., & Chen, J. (2024) · Nature Communications · doi:10.1038/s41467-024-48632-3 · Cited by 34
Ruenraroengsak, P., Chen, S., Hu, S., Melbourne, J., Sweeney, S. S., Thorley, A. J., Skepper, J. N., Shaffer, M. S. P., Tetley, T. D., & Porter, A. E. (2016) · ACS Nano · doi:10.1021/acsnano.5b08218 · Cited by 33
FGF10 and Human Lung Disease Across the Life Spectrum
Prince, L. S. (2018) · Frontiers in Genetics · doi:10.3389/fgene.2018.00517 · Cited by 33
“In addition to the physiological roles of delivering oxygen to the systemic circulation and removing carbon dioxide, each of the cell populations in the lung play important roles in protecting against infection and repairing the lung following mechanical, chemical, or biological damage (Barkauskas et al., 2013; Chambe…”
BackgroundWang, Y., Li, Y., Zhang, P., Baker, S. T., Wolfson, M. R., Weiser, J. N., Tian, Y., & Shen, H. (2019) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1818522116 · Cited by 33
“By 30 dpi, there was substantial recovery of AECI and AECII, although T1α and SPC mRNA levels were still reduced compared with those before infection (Fig.”
BackgroundMethodInfluentialInterleukin-13 disrupts type 2 pneumocyte stem cell activity
Glisinski, K., Schlobohm, A., Paramore, S. V., Birukova, A., Moseley, M. A., Foster, M. W., & Barkauskas, C. E. (2020) · JCI Insight · doi:10.1172/jci.insight.131232 · Cited by 32
“As we have previously shown (5), the vast majority of cells labeled in these mice are AEC2s; less than 1% of labeled cells are dual-positive SFTPC+SCGB1A1+ cuboidal cells in the terminal bronchioles (bronchoalveolar stem cells, or BASCs; ref.”
BackgroundMethodResultInfluentialSelf-citationVazquez‐Armendariz, A. I., Barroso, M. M., Agha, E. E., & Herold, S. (2022) · Cells · doi:10.3390/cells11091526 · Cited by 37
Epithelial Endoplasmic Reticulum Stress Enhances the Risk of Muc5b-Associated Lung Fibrosis
Dobrinskikh, E., Hennessy, C. E., Kurche, J. S., Kim, E.-J., Estrella, A. M., Cardwell, J., Yang, I. V., & Schwartz, D. A. (2022) · American Journal of Respiratory Cell and Molecular Biology · doi:10.1165/rcmb.2022-0252oc · Cited by 37
Stem Cells and the Bird Cochlea—Where Is Everybody?Preprint
Janesick, A., & Heller, S. (2018) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a033183 · Cited by 31
“In lung epithelia, signaling from the underlying stromal layer define the 1% of Wnt-responsive type II alveolar cells that serve as facultative stem cells (Barkauskas et al. 2013; Desai et al. 2014; Ouadah 2018).”
BackgroundKeeping it together: Pulmonary alveoli are maintained by a hierarchy of cellular programs
Logan, C. Y., & Desai, T. (2015) · BioEssays · doi:10.1002/bies.201500031 · Cited by 32
“On the other hand, when AT2 cells were labeled in bulk using amulticolor lineage reporter, and then a significant subset was acutely ablated, coarse foci of monochromatic AT2 cell clusters resulted [30].”
BackgroundZeng, L., Yang, X., Li, H.-S., Li, Y., Yang, C., Gu, W., Zhou, Y., Du, J., Wang, H.-Y., Sun, J., et al. (2016) · Respiratory Research · doi:10.1186/s12931-016-0480-y · Cited by 32
“verified that AEC2s are stem cells in adult lung [11].”
BackgroundLoss of Nrf2 promotes alveolar type 2 cell loss in irradiated, fibrotic lung
Traver, G. L., Mont, S., Gius, D. R., Lawson, W. E., Ding, G., Sekhar, K. R., & Freeman, M. L. (2017) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2017.08.026 · Cited by 31
“Type 2 cell repopulation following cytotoxic injury is dependent on the severity of injury [23] and is a consequence of alveolar type 2 self-renewal capacity [38], as well as regeneration by progenitor Club cells [44] and transdifferentiation of Hopx+ alveolar type 1 cells [45].”
BackgroundGuo, L., Karoubi, G., Duchesneau, P., Shutova, M. V., Sung, H.-K., Tonge, P., Bear, C., Rogers, I., Nagy, A., & Waddell, T. K. (2017) · Stem Cell Reports · doi:10.1016/j.stemcr.2017.10.022 · Cited by 33
“Endogenous progenitor cells exist in various organs, including the lung (Kim et al., 2005; Rawlins et al., 2009; Rock et al., 2009; Barkauskas et al., 2013; Vaughan et al., 2014; Jain et al., 2015).”
BackgroundWu, J., Chu, X., Chen, C., & Bellusci, S. (2018) · Frontiers in Genetics · doi:10.3389/fgene.2018.00545 · Cited by 32
“The growth of AT2 stem cells in Matrigel to form alveolosphere-like structures is drastically enhanced when co-cultured with LIFs (Barkauskas et al., 2013).”
BackgroundTang, Z., Gao, J., Wu, J., Zeng, G., Liao, Y., Song, Z., Liang, X., Hu, J., Hu, Y., Liu, M., et al. (2021) · Stem Cell Research & Therapy · doi:10.1186/s13287-021-02469-5 · Cited by 33
“Mouse genetic studies suggest that lung epithelial cells, especially alveolar type 2 cells, play a key role in initiating the pathogenic process and excessive pulmonary fibroblast proliferation and extracellular matrix (ECM) deposition leads to the destruction of alveolar structure [3, 38, 41].”
BackgroundLakhdar, R., Mumby, S., Abubakar-Waziri, H., Porter, A., Adcock, I., & Chung, K. (2022) · Environmental Pollution · doi:10.1016/j.envpol.2022.119323 · Cited by 26
Epigenetic basis of oncogenic-Kras-mediated epithelial-cellular proliferation and plasticity
Murthy, P. K. L., Xi, R., Mendoza, D. A., Everitt, J. I., Koçak, D. D., Kobayashi, Y., Bözec, A., Vicent, S., Ding, S., Crawford, G. E., et al. (2022) · Developmental Cell · doi:10.1016/j.devcel.2022.01.006 · Cited by 29
Weeratunga, P. N., Denney, L., Bull, J. A., Repapi, E., Sergeant, M. J., Etherington, R. E., Vuppusetty, C., Turner, G. D. H., Clelland, C., Woo, J., et al. (2023) · Nature Communications · doi:10.1038/s41467-023-42421-0 · Cited by 32
“The ability of these cells to differentiate to type 1 alveolar epithelium is critical to normal repair and alveolar regeneration after viral induced damage 30 – 32 .”
McCall, A. S., Gutor, S. S., Tanjore, H., Burman, A., Sherrill, T. P., Chapman, M., Calvi, C. L., Han, D., Camarata, J. E., Hunt, R. P., et al. (2025) · Science Translational Medicine · doi:10.1126/scitranslmed.adk8623 · Cited by 35
Alveolar Epithelium and Pulmonary Surfactant
Mason, R. J., & Dobbs, L. G. (2015) · Elsevier eBooks · doi:10.1016/b978-1-4557-3383-5.00008-7 · Cited by 31
“More recently, the ability of TII cells to proliferate and transdifferentiate into TI cells was documented by lineage tracing techniques in mouse lung.(46) This recent report demonstrated that TII cells are the source of new TI cells and TII cells under normal conditions and under conditions of mild injury.”
Ahmed, E., Sansac, C., Assou, S., Gras, D., Petit, A., Vachier, I., Chanez, P., Vos, J. D., & BOURDIN, A. A. (2017) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2017.10.002 · Cited by 34
You Say You Want a Resolution (of Fibrosis)
Atabai, K., Yang, C. D., & Podolsky, M. J. (2020) · American Journal of Respiratory Cell and Molecular Biology · doi:10.1165/rcmb.2020-0182tr · Cited by 30
“cells (156) isolated from IPF tissue have impaired regenerative ability compared with healthy tissue (157), highlighting the”
BackgroundLeveraging 3D Model Systems to Understand Viral Interactions with the Respiratory Mucosa
Iverson, E., Kaler, L., Agostino, E. L., Song, D., Duncan, G. A., & Scull, M. A. (2020) · Viruses · doi:10.3390/v12121425 · Cited by 28
“found that primary human type II alveolar epithelial cells only grew into self-renewing alveolar organoids when co-cultured with a fetal human pulmonary fibroblast cell line, and that mature type II alveolar cells could be found even after subculture [66].”
BackgroundWNT Signalling in Lung Physiology and Pathology
Hu, Y., Ciminieri, C., Hu, Q., Lehmann, M., Königshoff, M., & Gosens, R. (2021) · Handbook of experimental pharmacology · doi:10.1007/164_2021_521 · Cited by 31
Metadata
- Authors
- Barkauskas, C. E., Cronce, M. J., Rackley, C. R., Bowie, E. J., Keene, D. R., Stripp, B. R., Randell, S. H., Noble, P. W., & Hogan, B. L. M.
- Affiliations
- Duke University (US)
- Shriners Hospitals for Children (US)
- Cedars-Sinai Medical Center (US)
- University of North Carolina at Chapel Hill (US)
- ORCID
- Venue
- Journal of Clinical Investigation
- Published
- 2013-06-10
- Volume
- 123
- Issue
- 7
- Pages
- 3025-3036
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC3696553
- OpenAlex
- W2050308681
- Cited by
- 1,776
- References
- 49
- Citations by year
- 2026: 126 · 2025: 167 · 2024: 167 · 2023: 179 · 2022: 193 · 2021: 207 · 2020: 181 · 2019: 121 · 2018: 109 · 2017: 99 · 2016: 74 · 2015: 78 · 2014: 60 · 2013: 12
- FWCI
- 60.69
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
- UNC Libraries
- Funders
- National Heart, Lung, and Blood Institute (P01HL108793, T32HL007538, R37HL071303, U01HL111018, R01HL060539, T32HL098099, UO1HL111018)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Neonatal Respiratory Health Research
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Interstitial Lung Diseases and Idiopathic Pulmonary Fibrosis
- Health Sciences › Medicine › Surgery › Transplantation: Methods and Outcomes
- Keywords
- alveolar stem cells, lung regeneration, alveolar repair, clonal lineage tracing, surfactant protein C, self-renewal, clonal expansion, HOPX, lipofibroblasts, stem cell niche, lung injury
- MeSH terms
- Animals, Cell Differentiation, Cells, Cultured, Lung, Mice, Inbred C57BL, Mice, Transgenic, Stromal Cells, Coculture Techniques, Cell Lineage, Receptor, Platelet-Derived Growth Factor alpha, Cell Proliferation, Mice, Adult Stem Cells, Stem Cell Niche, Lung Injury, Alveolar Epithelial Cells, Mice, 129 Strain
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