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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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MethodLung organoids, useful tools for investigating epithelial repair after lung injury
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Matrix, Mesenchyme, and Mechanotransduction
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BackgroundMethodInfluentialLysoTracker is a marker of differentiated alveolar type II cells
Velden, J. L. V. D., Bertoncello, I., & McQualter, J. L. (2013) · Respiratory Research · doi:10.1186/1465-9921-14-123 · Cited by 66
Organoid models in lung regeneration and cancer
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“ATII cells produce surfactant protein C (SPC), a circulating surfactant protein in alveoli, and are the progenitor cells for ATI cells [45].”
BackgroundMicrostructured Hydrogels to Guide Self‐Assembly and Function of Lung Alveolospheres
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The Hedgehog Signaling Pathway in Idiopathic Pulmonary Fibrosis: Resurrection Time
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“AECIIs are capable of self-renewing and self-differentiation into AECIs [75].”
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“AT2 cells are considered as alveolar stem cells [158].”
The lung mesenchyme in development, regeneration, and fibrosis
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“These studies also established that PDGFRα+ stromal cells, a population that includes LIFs in the adult lung, represent an important mesenchymal niche for AT2s (72).”
BackgroundParis, A. J., Liu, Y., Mei, J., Dai, N., Guo, L., Spruce, L. A., Hudock, K. M., Brenner, J. S., Zacharias, W. J., Mei, H. D., et al. (2016) · American Journal of Physiology-Lung Cellular and Molecular Physiology · doi:10.1152/ajplung.00327.2016 · Cited by 65
“As previous studies have identified the AT2 cell as a key source of AT1 cells following lung injury (9, 42), we next sought to evaluate how the loss of neutrophils would impact AT2 cell proliferation.”
BackgroundResultMicroRNA-29c Prevents Pulmonary Fibrosis by Regulating Epithelial Cell Renewal and Apoptosis
Xie, T., Liang, J., Geng, Y., Liu, N., Kurkciyan, A., Kulur, V., Leng, D., Deng, N., Liu, Z., Song, J., et al. (2017) · American Journal of Respiratory Cell and Molecular Biology · doi:10.1165/rcmb.2017-0133oc · Cited by 64
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“A subset of alveolar epithelial type (AEC) 2 cells are distal lung progenitor cells (LPCs) that have the ability to self-renew and differentiate in vivo and form alveolospheres in vitro, harboring both AEC1s and AEC2s [10].”
BackgroundAros, C. J., Vijayaraj, P., Pantoja, C. J., Bisht, B., Meneses, L. K., Sandlin, J. M., Tse, J. A., Chen, M. W., Purkayastha, A., Shia, D. W., et al. (2020) · Cell stem cell · doi:10.1016/j.stem.2020.06.019 · Cited by 68
“In contrast, the non-cartilaginous bronchiolar, alveolar, and bronchioalveolar tissues of the airway have region-specific adult stem cell populations (Barkauskas et al., 2013; Desai et al., 2014; Kim et al., 2005; Rawlins et al., 2009) capable of self-renewal and differentiation.”
BackgroundKovács, T., Csöngei, V., Feller, D., Ernszt, D., Smuk, G., Sárosi, V., Jakab, L., Kvell, K., Bartis, D., & Pongracz, J. E. (2014) · Aging Cell · doi:10.1111/acel.12240 · Cited by 66
“ATII cells are capable of transdifferentiation into ATI cells (Crosby & Waters, 2010; Rock et al., 2011; Barkauskas et al., 2013) providing the gas exchange surface of alveoli.”
BackgroundWNT Signaling in Lung Repair and Regeneration.
Raslan, A., & Yoon, J. K. (2020) · PubMed Central · doi:10.14348/molcells.2020.0059 · Cited by 63
“Both in vitro and in vivo pulse-labeling experiments have demonstrated that AT2 cells can proliferate and differentiate into AT1 cells (Barkauskas et al., 2013; Desai et al., 2014; Olajuyin et al., 2019) (Table 1).”
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“Notably, a number of pro-inflammatory and pro-apoptotic genes were identified as driver genes, along with a recently discovered AT2 surface marker, CD74, which is helpful for discriminating AT2s from AT1s [33] (Additional file 2: Fig.”
BackgroundInfluentialVerstappe, J., & Berx, G. (2023) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2023.02.001 · Cited by 61
Ma, L., Thapa, B. R., Suer, J. A. L., Tilston-Lünel, A., Herriges, M. J., Berical, A. C., Beermann, M. L., Wang, F., Bawa, P., Kohn, A., et al. (2023) · Cell stem cell · doi:10.1016/j.stem.2023.07.014 · Cited by 66
Self-citationLung repair and regeneration: Advanced models and insights into human disease
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Yin, Y., & Ornitz, D. M. (2020) · Science Signaling · doi:10.1126/scisignal.aay4353 · Cited by 63
“Production of HOPX, an AT1 cell marker (46), was observed in the distal epithelium of control lungs and was sparsely distributed throughout the epithelium of FGF9-overexpressing lungs (fig.”
BackgroundEmerging Roles of Airway Epithelial Cells in Idiopathic Pulmonary Fibrosis
Chakraborty, A., Mastalerz, M., Ansari, M., Schiller, H. B., & Staab-Weijnitz, C. A. (2022) · Cells · doi:10.3390/cells11061050 · Cited by 68
“Basal cells are established as the main human progenitor cells for all cell types in the pseudostratified epithelium lining the conducting airways [6] while AT2 cells give rise to AT1 cells in the alveoli [7].”
BackgroundFatty Acid Metabolism and Idiopathic Pulmonary Fibrosis
Geng, J., Liu, Y., Dai, H., & Wang, C. (2022) · Frontiers in Physiology · doi:10.3389/fphys.2021.794629 · Cited by 61
Strategies for Whole Lung Tissue Engineering
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“murine type II cells to that of an alveolar stem cell [62].”
BackgroundHegab, A. E., Arai, D., Gao, J., Kuroda, A., Yasuda, H., Ishii, M., Naoki, K., Soejima, K., & Betsuyaku, T. (2015) · Stem Cell Research · doi:10.1016/j.scr.2015.05.005 · Cited by 62
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“It has been shown that Pdgfra fibroblasts accelerate the conversion of AEC2s to AEC1s in vitro (Barkauskas et al., 2013).”
BackgroundInfluentialChen, Q., Rehman, J., Chan, M., Fu, P., Dudek, S. M., Natarajan, V., Malik, A. B., & Liu, Y. (2020) · Cell Reports · doi:10.1016/j.celrep.2020.107828 · Cited by 62
“AT2 cells are normally quiescent with a slow turnover rate (Barkauskas et al., 2013; Desai et al., 2014).”
BackgroundRabata, A., Fedr, R., Souček, K., Hampl, A., & Koledova, Z. S. (2020) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2020.00574 · Cited by 61
Pathophysiological mechanisms of ARDS: a narrative review from molecular to organ-level perspectives
Zhou, K., Qin, Q., & Lu, J. (2025) · Respiratory Research · doi:10.1186/s12931-025-03137-5 · Cited by 65
Targeted Type 2 Alveolar Cell Depletion. A Dynamic Functional Model for Lung Injury Repair
Garcia, O., Hiatt, M. J., Lundin, A., Lee, J., Reddy, R., Navarro, S., Kikuchi, A., & Driscoll, B. (2015) · American Journal of Respiratory Cell and Molecular Biology · doi:10.1165/rcmb.2014-0246oc · Cited by 61
Evidence for Scgb1a1+ Cells in the Generation of p63+ Cells in the Damaged Lung Parenchyma
Zheng, D., Yin, L., & Chen, J. (2013) · American Journal of Respiratory Cell and Molecular Biology · doi:10.1165/rcmb.2013-0327oc · Cited by 61
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Targeting Alveolar Repair in Idiopathic Pulmonary Fibrosis
Ptasinski, V., Stegmayr, J., Belvisi, M. G., Wagner, D. E., & Murray, L. A. (2021) · American Journal of Respiratory Cell and Molecular Biology · doi:10.1165/rcmb.2020-0476tr · Cited by 60
“renew and transdifferentiate into AEC1s, thereby maintaining the alveolar epithelium during homeostasis and injury (41, 42).”
BackgroundPrimary human organoids models: Current progress and key milestones
Calà, G., Sina, B., Coppi, P. D., Giobbe, G. G., & Gerli, M. (2023) · Frontiers in Bioengineering and Biotechnology · doi:10.3389/fbioe.2023.1058970 · Cited by 62
“Different stem cell pools reside in the lung epithelium (Rock et al., 2009; Barkauskas et al., 2013), which is canonically divided into airway and alveolar.”
BackgroundMechanisms of DNA damage repair in adult stem cells and implications for cancer formation
Weeden, C. E., & Asselin-Labat, M.-L. (2017) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2017.10.015 · Cited by 61
Abo, K. M., Sainz de Aja, J., Lindstrom-Vautrin, J., Alysandratos, K.-D., Richards, A., Garcia-de-Alba, C., Huang, J., Hix, O. T., Werder, R. B., Bullitt, E., et al. (2022) · JCI Insight · doi:10.1172/jci.insight.155589 · Cited by 48
“Primary human AT2s can be cultured and passaged in vitro as 3-dimensional (3D) organoids (11, 12) but are”
BackgroundCell-based therapy for idiopathic pulmonary fibrosis
Lu, Q., & El-Hashash, A. H. K. (2019) · Stem Cell Investigation · doi:10.21037/sci.2019.06.09 · Cited by 59
“AECII cells can selfreplicate and serve as adult stem cells that differentiate into AECI cells during normal homeostatic turnover and when the AECI cell number is reduced by injury (40).”
BackgroundToulmin, S. A., Bhadiadra, C., Paris, A. J., Lin, J. H., Katzen, J. B., Basil, M. C., Morrisey, E. E., Worthen, G. S., & Eisenlohr, L. C. (2021) · Nature Communications · doi:10.1038/s41467-021-23619-6 · Cited by 60
The Challenge of Long-Term Cultivation of Human Precision-Cut Lung Slices
Preuß, E. B., Schubert, S., Werlein, C., Stark, H., Braubach, P., Höfer, A., Plucinski, E. K., Shah, H., Geffers, R., Sewald, K., et al. (2021) · American Journal Of Pathology · doi:10.1016/j.ajpath.2021.10.020 · Cited by 59
Moimas, S., Salton, F., Kośmider, B., Ring, N., Volpe, M. C., Bahmed, K., Braga, L., Rehman, M., Vodret, S., Graziani, M. L., et al. (2019) · ERJ Open Research · doi:10.1183/23120541.00138-2019 · Cited by 62
FGFR2 Is Required for AEC2 Homeostasis and Survival after Bleomycin-induced Lung Injury
Dorry, S. J., Ansbro, B. O., Ornitz, D. M., Mutlu, G. M., & Guzy, R. D. (2019) · American Journal of Respiratory Cell and Molecular Biology · doi:10.1165/rcmb.2019-0079oc · Cited by 60
“Over 90% of AEC2s are lineage labeled with GFP after tamoxifen treatment of control Sftpc;ROSA mice (not shown) (32).”
BackgroundInfluentialRecent advances in human respiratory epithelium models for drug discovery
Yaqub, N., Wayne, G. J., Birchall, M., & Song, W. (2021) · Biotechnology Advances · doi:10.1016/j.biotechadv.2021.107832 · Cited by 64
Immune determinants of chronic sequelae after respiratory viral infection
Narasimhan, H., Wu, Y., Goplen, N. P., & Sun, J. (2022) · Science Immunology · doi:10.1126/sciimmunol.abm7996 · Cited by 61
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“They act as resident stem cells capable of proliferating and differentiating into alveolar epithelial type-1 cells (AT1 cells), which are crucial for efficient gas exchange and for the regeneration of new alveoli after injury [28, 29].”
Macrophage peroxisomes guide alveolar regeneration and limit SARS-CoV-2 tissue sequelae
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Surfactant protein C dampens inflammation by decreasing JAK/STAT activation during lung repair
Jin, H., Ciechanowicz, A. K., Kaplan, A. R., Wang, L., Zhang, P.-X., Lu, Y.-C., Tobin, R. E., Tobin, B. A., Cohn, L. E., Zeiss, C. J., et al. (2018) · American Journal of Physiology-Lung Cellular and Molecular Physiology · doi:10.1152/ajplung.00418.2017 · Cited by 58
“SPC is expressed primarily in alveolar type 2 (AT2) cells, the facultative stem cells in the alveoli (4).”
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Durable alveolar engraftment of PSC-derived lung epithelial cells into immunocompetent mice
Herriges, M. J., Yampolskaya, M., Thapa, B. R., Lindstrom-Vautrin, J., Wang, F., Huang, J., Na, C.-L., Ma, L., Montminy, M. M., Bawa, P., et al. (2023) · Cell stem cell · doi:10.1016/j.stem.2023.07.016 · Cited by 60
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“…the population of ATII cells possesses properties of stem cells within the adult lung alveolar epithelium in vivo (Adamson and Bowden, 1974; Chapman et al., 2011; Barkauskas et al., 2013; D is ea se M o d el s & M ec h an is m s Treutlein et al., 2014; Desai et al., 2014; Vaughan et al., 2015).”
InfluentialStem Cells in Lung Injury and Repair
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Pulmonary fibrosis: Emerging diagnostic and therapeutic strategies
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“In addition, in the context of bleomycin injury, prelabeled Scgb1a1 cells were shown to give rise to AECII in the fibrotic regions [74].”
BackgroundInfluentialProgress towards non-small-cell lung cancer models that represent clinical evolutionary trajectories
Hynds, R. E., Frese, K. K., Pearce, D. R., Gronroos, E. C., Dive, C., & Swanton, C. (2021) · Open Biology · doi:10.1098/rsob.200247 · Cited by 59
“org/journal/rs 6 allowed serial passaging [67,101], limiting their utility for cancer modelling.”
BackgroundA Machine-Generated View of the Role of Blood Glucose Levels in the Severity of COVID-19
Logette, E., Lorin, C., Favreau, C., Oshurko, E., Coggan, J. S., Casalegno, F., Sy, M. F., Monney, C., Bertschy, M., Delattre, É., et al. (2021) · Frontiers in Public Health · doi:10.3389/fpubh.2021.695139 · Cited by 58
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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