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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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“A uthor M anuscript A uthor M anuscript A uthor M anuscript A uthor M anuscript advances in ex vivo human lung organoid culture systems provide a unique opportunity to define mechanisms important for human lung cell differentiation and self-renewal (Barkauskas et al. 2013, Lee et al. 2014).”
BackgroundOpportunities for organoids as new models of aging
Hu, J. L., Todhunter, M. E., LaBarge, M. A., & Gartner, Z. J. (2017) · The Journal of Cell Biology · doi:10.1083/jcb.201709054 · Cited by 92
“…and Davies, 2012; Freedman et al., 2015; Morizane et al., 2015 Lung Human, mouse Human, mouse hiPSC, mouse Moore et al., 2005; Wu et al., 2010; Barkauskas et al., 2013; Dye et al., 2015; Hegab et al., 2015 Muscle: skeletal, cardiac Human, rat, mouse hiPSC Lee et al., 2008; Madden et al.,…”
Disease modeling of pulmonary fibrosis using human pluripotent stem cell-derived alveolar organoids
Suezawa, T., Kanagaki, S., Moriguchi, K., Masui, A., Nakao, K., Toyomoto, M., Tamai, K., Mikawa, R., Hirai, T., Murakami, K., et al. (2021) · Stem Cell Reports · doi:10.1016/j.stemcr.2021.10.015 · Cited by 92
“Alveolar type 2 (AT2) cells are major tissue stem cells capable of secreting pulmonary surfactant in alveoli (Barkauskas et al., 2013).”
BackgroundThe insert sequence in SARS-CoV-2 enhances spike protein cleavage by TMPRSSPreprint
Meng, T., Cao, H., Zhang, H., Kang, Z., Xu, D., Gong, H., Wang, J., Li, Z., Cui, X., Xu, H., et al. (2020) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2020.02.08.926006 · Cited by 91
Stem cell-based Lung-on-Chips: The best of both worlds?
Nawroth, J. C., Barrile, R., Conegliano, D., van Riet, S., Hiemstra, P. S., & Villenave, R. (2018) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2018.07.005 · Cited by 89
“Lung organoids derived from human primary lung tissues, embryonic stem cells (ESCs) or induced pluripotent stem cells (iPSCs) are also referred to as tracheospheres, bronchospheres, and pneumospheres (or alveolospheres), and have been successfully employed to study lung development and pathophysiology [19, [38] [39] […”
BackgroundLung regeneration: a tale of mice and men
Basil, M. C., & Morrisey, E. E. (2019) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2019.11.006 · Cited by 87
“Multiple studies have highlighted the role for AT2 cells in promoting alveolar epithelial regeneration despite the fact that these functionally mature cells exhibit only slow turn-over under normal physiologic conditionsin mouse and humans [39,40] [41,38].”
BackgroundInfluentialLee, J.-Y., Jang, J., Park, S., & Yang, S. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22168406 · Cited by 89
Expansion of hedgehog disrupts mesenchymal identity and induces emphysema phenotype
Wang, C., de Mochel, N. R., Christenson, S. A., Cassandras, M., Moon, R. H., Brumwell, A. N., Byrnes, L. E., Li, A., Yokosaki, Y., Shan, P., et al. (2018) · Journal of Clinical Investigation · doi:10.1172/jci99435 · Cited by 79
Bowdish, D. M. E. (2018) · CHEST Journal · doi:10.1016/j.chest.2018.09.003 · Cited by 89
“Once lung disease (ie, COPD, pulmonary fibrosis, lung cancer) is present, elevated levels of the senescence marker p16 and shorter telomere length, a cardinal sign of cellular senescence, is apparent in AECs.(34,42) Exogenous insults such as bleomycin and cigarette smoke increase expression of these markers,(42-45) an…”
BackgroundShah, T. G., Predescu, D. N., & Predescu, S. A. (2019) · Clinical and Translational Medicine · doi:10.1186/s40169-019-0242-9 · Cited by 87
“Evidence indicates that in disease, the LR-MSCs migrate from their in-tissue niche into the alveolar space and are abundant and recoverable from the BAL fluid [50, 51].”
BackgroundLung Stem and Progenitor Cells in Tissue Homeostasis and Disease
Leeman, K. T., Brainson, C. F., & Kim, C. F. (2014) · Current topics in developmental biology/Current Topics in Developmental Biology · doi:10.1016/b978-0-12-416022-4.00008-1 · Cited by 89
Advanced human developmental toxicity and teratogenicity assessment using human organoid models
Li, M., Gong, J., Gao, L., Zou, T., Kang, J., & Xu, H. (2022) · Ecotoxicology and Environmental Safety · doi:10.1016/j.ecoenv.2022.113429 · Cited by 84
Chu, K.-A., Wang, S.-Y., Yeh, C., Fu, T.-W., Fu, Y.-Y., Ko, T.-L., Chiu, M.-M., Chen, T.-H., Tsai, P., & Fu, Y.-S. (2019) · Theranostics · doi:10.7150/thno.33741 · Cited by 85
“Type II alveolar epithelial cells (AEC2s) proliferate and transdifferentiate into Type I cells (AEC1s) at a slow pace to repair damaged alveoli [7, 8].”
BackgroundVascular Niche in Lung Alveolar Development, Homeostasis, and Regeneration
Mammoto, A., & Mammoto, T. (2019) · Frontiers in Bioengineering and Biotechnology · doi:10.3389/fbioe.2019.00318 · Cited by 85
“, 1993; Torday and Rehan, 2016), but also function as progenitor cells for AT1 cells (Evans et al., 1973, 1975; Barkauskas et al., 2013).”
BackgroundGeneration of human alveolar epithelial type I cells from pluripotent stem cells
Burgess, C. L., Huang, J., Bawa, P., Alysandratos, K., Minakin, K., Ayers, L. J., Morley, M. P., Babu, A., Villacorta-Martín, C., Yampolskaya, M., et al. (2024) · Cell stem cell · doi:10.1016/j.stem.2024.03.017 · Cited by 98
“…shared similar qualitative clustered expression patterns to published mouse datasets 38,39 ; however, well-characterized mouse markers, HOPX, AQP5, and IGFBP2, 7,34,40 were expressed in other epithelial cells, such as AT2s for HOPX and airway cells for AQP5 and IGFBP2 (Figures 1B–1D and S1B).”
BackgroundHung, L., Sen, D., Oniskey, T. K., Katzen, J. B., Cohen, N. A., Vaughan, A. E., Nieves, W., Urisman, A., Beers, M. F., Krummel, M. F., et al. (2018) · Mucosal Immunology · doi:10.1038/s41385-018-0096-2 · Cited by 84
Inal, J. M. (2020) · Clinical Science · doi:10.1042/cs20200623 · Cited by 86
Pulmonary alveolar regeneration in adult COVID-19 patients
Chen, J., Wu, H., Yu, Y., & Tang, N. (2020) · Cell Research · doi:10.1038/s41422-020-0369-7 · Cited by 81
A lung tropic AAV vector improves survival in a mouse model of surfactant B deficiency
Kang, M. H., van Lieshout, L. P., Xu, L., Domm, J. M., Vadivel, A., Renesme, L., Mühlfeld, C., Hurskainen, M., Mižíková, I., Pei, Y., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-17577-8 · Cited by 85
Chiu, M. C., Li, C., Liu, X., Yu, Y., Huang, J., Wan, Z., Xiao, D., Chu, H., Cai, J., Zhou, B., et al. (2022) · Cell Discovery · doi:10.1038/s41421-022-00422-1 · Cited by 85
An interactive murine single-cell atlas of the lung responses to radiation injury
Curras-Alonso, S., Soulier, J., Defard, T., Weber, C., Heinrich, S., Laporte, H., Leboucher, S., Lameiras, S., Dutreix, M., Favaudon, V., et al. (2023) · Nature Communications · doi:10.1038/s41467-023-38134-z · Cited by 89
Targeted alveolar regeneration with Frizzled-specific agonists
Nabhan, A. N., Webster, J. D., Adams, J., Blazer, L. L., Everrett, C., Eidenschenk, C., Arlantico, A., Fleming, I., Brightbill, H. D., Wolters, P. J., et al. (2023) · Cell · doi:10.1016/j.cell.2023.05.022 · Cited by 83
“Alveoli are maintained by self-renewing alveolar type 2 (AT2) stem cells that secrete surfactant and give rise to squamous, gas-exchanging AT1 cells.(4,5) AT2 stem cell failure causes epithelial erosion and an opportunistic expansion of fibroblasts, which compromises the surface for gas exchange.”
p63: a crucial player in epithelial stemness regulation
Li, Y., Giovannini, S., Wang, T., Fang, J., Li, P., Shao, C., Wang, Y., Agostini, M., Bove, P., Mauriello, A., et al. (2023) · Oncogene · doi:10.1038/s41388-023-02859-4 · Cited by 84
“Upon mild-to-moderate pulmonary injury, surviving AT2s self-renew and differentiate into oxygen-exchanging AT1 population to carry out functionally bene fi cial tissue regeneration [110].”
BackgroundEndale, M., Ahlfeld, S. K., Bao, E. L., Chen, X., Green, J., Bess, Z., Weirauch, M. T., Xu, Y. J., & Perl, A. T. (2017) · Developmental Biology · doi:10.1016/j.ydbio.2017.03.020 · Cited by 82
Manevski, M., Muthumalage, T., Devadoss, D., Sundar, I. K., Wang, Q., Singh, K. P., Unwalla, H. J., Chand, H. S., & Rahman, I. (2020) · Redox Biology · doi:10.1016/j.redox.2020.101443 · Cited by 87
Weiner, A. I., Jackson, S. R., Zhao, G., Quansah, K. K., Farshchian, J. N., Neupauer, K. M., Littauer, E. Q., Paris, A. J., Liberti, D. C., Worthen, G. S., et al. (2019) · npj Regenerative Medicine · doi:10.1038/s41536-019-0080-9 · Cited by 79
“AT2 cells can self-renew and differentiate into alveolar type1 (AT1) cells, thus producing essential surfactant and providing a source of oxygen-exchanging epithelial AT1 cells.(1,2) However, this response is imperfect and the lung also exhibits aberrant tissue remodeling that results in the appearance of ectopic cell…”
Repair and regeneration of the alveolar epithelium in lung injury
Wang, Y., Wang, L., Ma, S., Cheng, L. C., & Yu, G. (2024) · The FASEB Journal · doi:10.1096/fj.202400088r · Cited by 92
“…modulates the differentiation process [112] Mesenchymal cells niche PDGFR α + lipofibroblasts support the growth and differentiation of AT2 cells [117] Interstitial cells secrete IL-6 and FGF7 promoting AT2 cell proliferation and differentiation [118] Interstitial cells secrete BMP4 inhibiting…”
BackgroundKLF4 regulates adult lung tumor-initiating cells and represses K-Ras-mediated lung cancer
Yu, T., Chen, X., Zhang, W., Liu, J., Avdiushko, R., Napier, D. L., Liu, A., Neltner, J. H., Wang, C., Cohen, D. A., et al. (2015) · Cell Death and Differentiation · doi:10.1038/cdd.2015.85 · Cited by 81
“After birth, AT2 cells functions as stem cells in the lung.(20,21) The self-renewal of AT2 cells is regulated by EGFR and K-ras signals.”
BackgroundMolecular programs of fibrotic change in aging human lung
Lee, S., Islam, M. N., Boostanpour, K., Aran, D., Jin, G., Christenson, S., Matthay, M. A., Eckalbar, W. L., DePianto, D. J., Arron, J. R., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-26603-2 · Cited by 78
“Type 2 cells are thought to be 108 necessary for epithelial renewal in the lung, even at steady state.(28) Collectively, these findings 109 support a DNA damage response resulting from telomere shortening, leading to epithelial 110 senescence and pro-fibrotic pathway activation characterized by expansion of the mesenc…”
BackgroundNg-Blichfeldt, J.-P., Schrik, A., Kortekaas, R. K., Noordhoek, J. A., Heijink, I. H., Hiemstra, P. S., Stolk, J. N., Königshoff, M., & Gosens, R. (2018) · EBioMedicine · doi:10.1016/j.ebiom.2018.09.002 · Cited by 80
“A) Schematic of mouse organoid experimental setup, based on [5,40,41].”
MethodGérard, L., Lecocq, M., Bouzin, C., Hoton, D., Schmit, G., Pereira, J. P., Montiel, V., Planté-Bordeneuve, T., Laterre, P., & Pilette, C. (2021) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/rccm.202012-4461oc · Cited by 79
Choi, J., Jang, Y. J., Dabrowska, C., Iich, E., Evans, K. V., Hall, H., Janes, S. M., Simons, B. D., Koo, B., Kim, J., et al. (2021) · Nature Cell Biology · doi:10.1038/s41556-021-00742-6 · Cited by 77
Cohen, M., Brumwell, A. N., Ho, T. C., Garakani, K., Montas, G., Leong, D., Ding, V. W., Golden, J. A., Trinh, B. N., Jablons, D. M., et al. (2024) · Journal of Clinical Investigation · doi:10.1172/jci174598 · Cited by 91
“AEC2s normally have the dual function of producing pulmonary surfactant and differentiating into AEC1s, which line alveoli (9).”
Creating new ventures : A longitudinal investigation of the nascent venturing process
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The Role of Nrf2 in Pulmonary Fibrosis: Molecular Mechanisms and Treatment Approaches
Wang, Y., Wei, J., Deng, H., Zheng, L., Yang, H. Y., & Lv, X. (2022) · Antioxidants · doi:10.3390/antiox11091685 · Cited by 80
“AT2 cells, which are considered as alveolar stem cells and can differentiate into AT1 cells [74], represent underlying initiating mechanisms responsible for PF in response to repetitive lung damage [75].”
BackgroundRegulation of the alveolar regenerative niche by amphiregulin-producing regulatory T cells
Kaiser, K. A., Loffredo, L. F., Santos-Alexis, K. D. L., Ringham, O. R., & Arpaia, N. (2023) · Journal of Experimental Medicine · doi:10.1084/jem.20221462 · Cited by 79
“…lung mesenchymal cells supports growth of alveolar organoids To determine whether the activation of EGFR in lung mesenchymal cells promotes alveolar regeneration, we employed an alveolar organoid culture system (Barkauskas et al., 2013; Lee et al., 2017; McQualter et al., 2010; Zepp et al., 2017).”
BackgroundMethodInfluentialWang, Z., Wei, D., Bin, E., Li, J., Jiang, K., Lv, T., Mao, X., Wang, F., Dai, H., & Tang, N. (2023) · Cell stem cell · doi:10.1016/j.stem.2023.07.007 · Cited by 82
Henry, E., Cores, J., Hensley, M. T., Anthony, S., Vandergriff, A. C., de Andrade, J. B. M., Allen, T. A., Caranasos, T. G., Lobo, L. J., & Cheng, K. (2015) · Stem Cells Translational Medicine · doi:10.5966/sctm.2015-0062 · Cited by 78
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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