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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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“Normally, AT2 cells exhibit minimal self-renewal activity, maintaining a constant ratio that provides them with inherent stemness to maintain the integrity of the alveolar barrier under pathological conditions [72,73].”
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Post, Y., Lu, C., Fletcher, R. B., Yeh, W., Nguyen, H., Lee, S., & Li, Y. (2024) · iScience · doi:10.1016/j.isci.2024.109938 · Cited by 18
Lung organoids in COPD: recent advances and future prospects
Huo, Y., He, S., & Chen, Y. (2025) · Respiratory Research · doi:10.1186/s12931-025-03138-4 · Cited by 18
“For example, lineage-tracing studies conducted following damage to the alveolar region by the chemotherapeutic drug bleomycin have demonstrated that Scgb1a1 + cells in the distal bronchioles proliferate and give rise to progeny in the alveoli with characteristics of AT2s and AT1s [25].”
InfluentialStromal heterogeneity in the adult lung delineated by single-cell genomics
Tsukui, T., & Sheppard, D. (2025) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00285.2025 · Cited by 16
Heterogeneity of Pulmonary Stem Cells
Lynch, T. J., Ievlev, V., & Parekh, K. R. (2019) · Advances in experimental medicine and biology · doi:10.1007/978-3-030-24108-7_6 · Cited by 16
Hermansky-Pudlak syndrome-2 alters mitochondrial homeostasis in the alveolar epithelium of the lung
Cuevas-Mora, K., Roque, W., Shaghaghi, H., Gochuico, B. R., Rosas, I. O., Summer, R. S., & Romero, F. (2021) · Respiratory Research · doi:10.1186/s12931-021-01640-z · Cited by 16
Pleiotropic Effects of Secretin: A Potential Drug Candidate in the Treatment of Obesity?
Laurila, S., Rebelos, E., Honka, M., & Nuutila, P. (2021) · Frontiers in Endocrinology · doi:10.3389/fendo.2021.737686 · Cited by 16
Zhang, K., Wang, L., Hong, X., Chen, H., Shi, Y., Liu, Y., Liu, J., & Liu, J. (2021) · Cells · doi:10.3390/cells10112892 · Cited by 16
iPSC-Derived Airway Epithelial Cells: Progress, Promise, and Challenges
Yu, F., Liu, F., Liang, X., Duan, L., Li, Q., Pan, G., Ma, C., Liu, M., Li, M., Wang, P., et al. (2022) · Stem Cells · doi:10.1093/stmcls/sxac074 · Cited by 16
Dada, L. A., Welch, L. C., Magnani, N., Ren, Z., Han, H., Brazee, P. L., Celli, D. A., Flozak, A. S., Weng, A., Maciel, M., et al. (2023) · JCI Insight · doi:10.1172/jci.insight.159331 · Cited by 16
“Clonal alveolar organoid assays were performed as described previously (13, 18).”
Bioengineering and Clinical Translation of Human Lung and its Components
Derman, İ. D., Singh, Y. P., Saini, S., Nagamine, M., Banerjee, D., & Ozbolat, I. T. (2023) · Advanced Biology · doi:10.1002/adbi.202200267 · Cited by 17
PFAS in PMs might be the escalating hazard to the lung health
Pan, Y., Mei, J., Jiang, J., Xu, K., Gao, X., Jiang, S., & Liu, Y. (2023) · Nano Research · doi:10.1007/s12274-023-6051-x · Cited by 18
Kutsuzawa, N., Ito, Y., Kagawa, S., Kohno, C., Takiguchi, H., & Asano, K. (2023) · PLoS ONE · doi:10.1371/journal.pone.0295684 · Cited by 18
Screening of factors inducing alveolar type 1 epithelial cells using human pluripotent stem cells
Ohnishi, Y., Masui, A., Suezawa, T., Mikawa, R., Hirai, T., Hagiwara, M., & Gotoh, S. (2024) · Stem Cell Reports · doi:10.1016/j.stemcr.2024.02.009 · Cited by 18
“Wnt signaling inhibitor and YAP/TAZ signaling activator were expected to be hits in the compound screening since we previously re-ported that XAV939, a suppressor of the canonical Wnt signalingviainhibitionoftankyrase,promotediAT1celldif-ferentiation from iAT2 cells in FD-AOs, and YAP/TAZ signaling is essential in AT1…”
InfluentialHarnessing the potential of lung stem cells for regenerative medicine
McQualter, J. L., Anthony, D., Bozinovski, S., Prêle, C. M., & Laurent, G. J. (2014) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/j.biocel.2014.10.012 · Cited by 16
McGowan, S. E. (2017) · Cell and Tissue Research · doi:10.1007/s00441-016-2542-3 · Cited by 16
“MRTF-A Myocardin-related transcription factor A Cell Tissue Res pneumonectomy and can support epithelial proliferation and differentiation after alveolar damage (Chen et al. 2012; Barkauskas et al. 2013).”
The Role of Radiation Induced Injury on Lung Cancer
Puukila, S., Thome, C., Brooks, A. L., Woloschak, G. E., & Boreham, D. R. (2017) · Cancers · doi:10.3390/cancers9070089 · Cited by 16
“The type II alveolar cells are thought to be the stem cells in the adult lung that maintain the integrity of the lung [31].”
BackgroundA novel mouse Cre‐driver line targeting Perilipin 2‐expressing cells in the neonatal lung
Ntokou, A., Szibor, M., Rodríguez‐Castillo, J. A., Quantius, J., Herold, S., Agha, E. E., Bellusci, S., Salwig, I., Braun, T. W., Voswinckel, R., et al. (2017) · genesis · doi:10.1002/dvg.23080 · Cited by 16
“The plateletderived growth factor receptor (PDGFR)a lineage can give rise to a part of lipofibroblasts during alveolarization and lipofibroblasts of the adult lung express PDGFRa (Barkauskas et al., 2013; Ntokou et al., 2015).”
BackgroundHegab, A. E., Ozaki, M., Meligy, F. Y., Nishino, M., Kagawa, S., Ishii, M., & Betsuyaku, T. (2018) · Journal of Tissue Engineering and Regenerative Medicine · doi:10.1002/term.2792 · Cited by 17
“For long, we and others (Barkauskas et al., 2013) have considered AT2 cells to be the stem cell of the alveolar compartment and thus used the AT2‐sorted or enriched WLCs for our in vitro studies.”
BackgroundMethodNakajima, K., Ono, M., Radović, U., Dizdarević, S., Tomizawa, S.-I., Kuroha, K., Naganatsu, G., Hoshi, I., Matsunaga, R., Shirakawa, T., et al. (2019) · Disease Models & Mechanisms · doi:10.1242/dmm.040139 · Cited by 16
“S4D) (Yin et al., 2006; Barkauskas et al., 2013).”
Ciechanowicz, A. K. (2019) · Advances in experimental medicine and biology · doi:10.1007/978-3-030-31206-0_13 · Cited by 16
Loss of Aryl Hydrocarbon Receptor Favors K-RasG12D-Driven Non-Small Cell Lung Cancer
Nacarino-Palma, A., Rejano-Gordillo, C. M., González-Rico, F. J., Ordiales-Talavero, A., Román, Á., Cuadrado, M., Bustelo, X. R., Merino, J. M., & Fernández‐Salguero, P. M. (2021) · Cancers · doi:10.3390/cancers13164071 · Cited by 16
“Type-II alveolar cells are considered lung stem cells with autorenewal capacity [32].”
BackgroundVerschelden, G., Noeparast, M., Noparast, M., Goossens, M. C., Lauwers, M., COTTON, F. J., Michel, C., Goyvaerts, C., & Hites, M. (2021) · International Immunopharmacology · doi:10.1016/j.intimp.2021.108163 · Cited by 16
Identification of targetable kinases in idiopathic pulmonary fibrosis
Higo, H., Ohashi, K., Tomida, S., Okawa, S., Yamamoto, H., Sugimoto, S., Senoo, S., Makimoto, G., Ninomiya, K., Nakasuka, T., et al. (2022) · Respiratory Research · doi:10.1186/s12931-022-01940-y · Cited by 18
“In particular, alveolar type II (AT2) cells play important roles in the pathogenesis of IPF because they act as progenitor cells and help in regeneration of the respiratory epithelium [11, 12].”
BackgroundPeng, D.-Y., Si, D., Zhang, R., Liu, J., Gou, H., Xia, Y., Tian, D., Dai, J., Yang, K., Liu, E., et al. (2017) · Genes & Diseases · doi:10.1016/j.gendis.2017.10.001 · Cited by 16
“The residual SMARCA4 expression in the homozygotes might probably occurred due to incomplete excision by SPC-Cre.(7) Moreover, the similarity of SMARCA4 expression between the SOSM4 and SOSM4D/þ was possibly caused by the same reason.”
BackgroundResultInfluentialSun, W., Zhao, B., He, Z., Chang, L., Song, W., & Chen, Y. (2025) · Communications Biology · doi:10.1038/s42003-024-07334-8 · Cited by 15
“ATII cells are the primary progenitors for ATI cells 5,22 .”
Stabilized Extracellular Vesicle Formulations for Inhalable Dry Powder Development
Jansen, E. M., van der Koog, L., Elferink, R. A. B., Rafie, K., Nagelkerke, A., Gosens, R., Frijlink, H. W., & Hinrichs, W. L. J. (2025) · Small · doi:10.1002/smll.202411096 · Cited by 16
Temporo-spatial cellular atlas of the regenerating alveolar niche in idiopathic pulmonary fibrosis
Weeratunga, P. N., Hunter, B., Sergeant, M. J., Bull, J. A., Clelland, C., Denney, L., Vuppusetty, C., Burgoyne, R. A., Woo, J., Hu, T., et al. (2025) · Nature Communications · doi:10.1038/s41467-025-61880-1 · Cited by 22
“…an expert thoracic lung pathologist and two pulmonologists to fi t the following criteria — histopathologically identi fi ed alveoli with (i) presence of cells and (ii) presenceoftypeIIalveolarmetaplasia(oft-usedasafeatureofalveolar regeneration 13,14 and (iii) lack of bronchi and bronchioles (Fig.”
Tissue regeneration: Unraveling strategies for resolving pathological fibrosis
Li, J., Wang, S., Yuan, J., Mao, X., Wang, X., Zhang, L., Dong, Q., Chen, Z., Wang, Y., & Tang, N. (2025) · Cell stem cell · doi:10.1016/j.stem.2025.10.002 · Cited by 19
An Optimized Method to Isolate Human Fibroblasts from Tissue for Ex Vivo Analysis
Waise, S., Parker, R., Rose-Zerilli, M. J. J., Layfield, D., Wood, O., West, J. J., Ottensmeier, C. H. H., Thomas, G. J., & Hanley, C. J. (2019) · BIO-PROTOCOL · doi:10.21769/bioprotoc.3440 · Cited by 16
“However, epithelial and non-immune stromal cells are usually cultured in vitro prior to analysis (Lurton et al., 1999; Koumas et al., 2003; Comhair et al., 2012; Barkauskas et al., 2013; Mackay et al., 2013).”
BackgroundLung development: AT1 and AT2 property
Chen, Y., Dong, Y., & Du, X. (2020) · Biocell · doi:10.32604/biocell.2020.08041 · Cited by 15
“A large number of animal experiments have shown that SPC+ AT2 cells can differentiate into AT1 cells to repair alveolar structures when alveolar cells are injured (Barkauskas et al., 2013; Nabhan et al., 2018) (Fig.”
BackgroundStem Cell–Derived Respiratory Epithelial Cell Cultures as Human Disease Models
Orr, J. C., & Hynds, R. E. (2021) · American Journal of Respiratory Cell and Molecular Biology · doi:10.1165/rcmb.2020-0440tr · Cited by 15
Pandey, S. K., Shteinfer‐Kuzmine, A., Caspi, V. C., & Shoshan‐Barmatz, V. (2022) · Frontiers in Oncology · doi:10.3389/fonc.2022.992260 · Cited by 15
“We analyzed the expression of the AT1 cell marker podoplanin, a membranal mucin-type sialoglycoprotein (25).”
BackgroundMethodInfluentialSierra, I., Pyfrom, S., Weiner, A. I., Zhao, G., Driscoll, A., Yu, X., Gregory, B. D., Vaughan, A. E., & Anguera, M. C. (2023) · Stem Cell Reports · doi:10.1016/j.stemcr.2022.12.005 · Cited by 15
“Upon injury, AT2s can proliferate, restore the loss of surfactant-producing cells, and differentiate to re-establish gas-exchanging alveolar type I cells (AT1s) (Barkauskas et al., 2013; Evans et al., 1975).”
BackgroundSuzuki, K., Imaoka, T., Tomita, M., Sasatani, M., Doi, K., Tanaka, S., Kai, M., Yamada, Y., & Kakinuma, S. (2023) · Journal of Radiation Research · doi:10.1093/jrr/rrad003 · Cited by 16
“surfactant protein C-positive (SFTPC-positive) AT2 cells function as alveolar progenitors and long-term stem cells and can give rise to AT1 cells [62, 63].”
BackgroundBoo, H., Min, H., Park, C., Park, J., Jeong, J. Y., Lee, S. Y., Kim, W., Lee, J., Oh, S., Park, R., et al. (2023) · Cancer Research · doi:10.1158/0008-5472.can-22-3543 · Cited by 16
Injury activated alveolar progenitors (IAAPs): the underdog of lung repair
Chong, L., Ahmadvand, N., Noori, A., Lv, Y., Chen, C., Bellusci, S., & Zhang, J. (2023) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-023-04789-6 · Cited by 15
Yang, Y., Chen, Y., Liu, Y., Ning, Z.-D., Zhang, Z., Zhang, Y., Xu, K., & Zhang, L. (2023) · Frontiers in Pharmacology · doi:10.3389/fphar.2023.1136761 · Cited by 15
Aryal, A., Noël, A., Khachatryan, L., Cormier, S. A., Chowdhury, P. H., Penn, A. L., Dugas, T. R., & Harmon, A. C. (2023) · Environmental Pollution · doi:10.1016/j.envpol.2023.122183 · Cited by 16
Stoian, M., Roman, A., Boeriu, A. M., Onișor, D. M., Bândilă, S. R., Babă, D.-F., Cocuz, I. G., Niculescu, R., Costan, A., Laszlo, S. Ș., et al. (2023) · Biomedicines · doi:10.3390/biomedicines11102637 · Cited by 15
“AECIIs express more abundant angiotensin-converting enzyme 2 (ACE2) receptors, resulting in the higher infectivity of these cells, which may explain the defective surfactant production and re-epithelization of the broncho-alveolar epithelium after injury [30–33].”
BackgroundZhang, X., Ali, M. S., Pantuck, M. A., Yang, X., Lin, C.-R., Bahmed, K., Kośmider, B., & Tian, Y. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1268078 · Cited by 15
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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