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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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Raghu, G., Collard, H. R., Egan, J. J., Martinez, F. J., Behr, J., Brown, K. K., Colby, T. V., Cordier, J.-F., Flaherty, K. R., Lasky, J. A., et al. (2011) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/rccm.2009-040gl · Cited by 7,186
Identification of Bronchioalveolar Stem Cells in Normal Lung and Lung Cancer
Kim, C. F. B., Jackson, E. L., Woolfenden, A. E., Lawrence, S., Babar, I., Vogel, S., Crowley, D. G., Bronson, R. T., & Jacks, T. (2005) · Cell · doi:10.1016/j.cell.2005.03.032 · Cited by 2,229
Snippert, H. J., van der Flier, L. G., Sato, T., van Es, J. H., van den Born, M., Kroon-Veenboer, C., Barker, N., Klein, A. M., van Rheenen, J., Simons, B. D., et al. (2010) · Cell · doi:10.1016/j.cell.2010.09.016 · Cited by 1,951
Basal cells as stem cells of the mouse trachea and human airway epithelium
Rock, J. R., Onaitis, M. W., Rawlins, E. L., Lu, Y., Clark, C. P., Xue, Y., Randell, S. H., & Hogan, B. L. M. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0906850106 · Cited by 1,591
Self-citationLgr5+ve Stem Cells Drive Self-Renewal in the Stomach and Build Long-Lived Gastric Units In Vitro
Barker, N., Huch, M., Kujala, P., van de Wetering, M., Snippert, H. J., van Es, J. H., Sato, T., Stange, D. E., Begthel, H., van den Born, M., et al. (2010) · Cell Stem Cell · doi:10.1016/j.stem.2009.11.013 · Cited by 1,547
Scale: a chemical approach for fluorescence imaging and reconstruction of transparent mouse brain
Hama, H., Kurokawa, H., Kawano, H., Ando, R., Shimogori, T., Noda, H., Fukami, K., Sakaue-Sawano, A., & Miyawaki, A. (2011) · Nature Neuroscience · doi:10.1038/nn.2928 · Cited by 1,154
Rock, J. R., Barkauskas, C. E., Cronce, M. J., Xue, Y., Harris, J. R., Liang, J., Noble, P. W., & Hogan, B. L. M. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1117988108 · Cited by 1,048
Self-citationIntestinal Stem Cell Replacement Follows a Pattern of Neutral Drift
López‐García, C., Klein, A. M., Simons, B. D., & Winton, D. J. (2010) · Science · doi:10.1126/science.1196236 · Cited by 660
Distinct contribution of stem and progenitor cells to epidermal maintenance
Mascré, G., Dekoninck, S., Drogat, B., Youssef, K. K., Brohée, S., Sotiropoulou, P. A., Simons, B. D., & Blanpain, C. (2012) · Nature · doi:10.1038/nature11393 · Cited by 586
Kumar, P., Hu, Y., Yamamoto, Y., Hoe, N. B., Wei, T. S., Mu, D., Sun, Y., Lim, S. J., Dagher, R., Zielonka, E. M., et al. (2011) · Cell · doi:10.1016/j.cell.2011.10.001 · Cited by 578
Flagged first, then by citations
Research works printed but not linked: 5
- Kauffman, 1980, Int Rev Exp Pathol., 22, 131
- Kapanci, 1969, Lab Invest., 20, 101
- Evans, 1973, Am J Pathol., 70, 175
- Murphy JR Corynebacterium diphtheriae. In: Baron S, ed. Medical Microbiology. 4th ed. Galveston, Texas, USA: University of Texas Medical Branch at Galveston; 1996 Chapter 32
- Kaplan, 1985, Am Rev Respir Dis., 132, 1307
Cited by
Sorted by citations
Items 401–500 of 1,000
COVID-19-Related ARDS: Key Mechanistic Features and Treatments
Selickman, J., Vrettou, C. S., Mentzelopoulos, S. D., & Marini, J. J. (2022) · Journal of Clinical Medicine · doi:10.3390/jcm11164896 · Cited by 61
“Upon reaching the alveoli, SARS-CoV-2 primarily affects alveolar type 2 (AT2) cells which, in health, are tasked with both production of pulmonary surfactant and regeneration of AT1 cells (which constitute the majority of the alveolar epithelium) [31].”
BackgroundAdvanced lung organoids for respiratory system and pulmonary disease modeling
Joo, H., Min, S., & Cho, S. (2024) · Journal of Tissue Engineering · doi:10.1177/20417314241232502 · Cited by 66
“39,68,69 For this reason, in several studies differentiating lung organoids, fibroblasts are often co-cultured to induce stable maintenance of AEC2 in alveolar organoids.”
BackgroundMethodThe mitochondria in lung fibrosis: friend or foe?
Malsin, E. S., & Kamp, D. W. (2018) · Translational research · doi:10.1016/j.trsl.2018.05.005 · Cited by 56
“Cellular senescence, in contrast to apoptosis, is the permanent arrest of cell proliferation depleting organs of vital stem cells, including lung AT2 cells, necessary for appropriate repair as well as releasing deleterious profibrotic signals (see for reviews).(14,15,96-99) Senescence can be induced by multiple metabo…”
BackgroundLung development and emerging roles for type 2 immunity
Loering, S., Cameron, G. J. M., Starkey, M. R., & Hansbro, P. M. (2018) · The Journal of Pathology · doi:10.1002/path.5211 · Cited by 54
“Recent in vitro studies showed that culture of mesenchymal lineages with AT2 cells results in the formation of organoids and promotes AT2 self-renewal and differentiation into AT1 cells [35,36].”
BackgroundArif, T., Paul, A., Krelin, Y., Shteinfer‐Kuzmine, A., & Shoshan‐Barmatz, V. (2018) · Cancers · doi:10.3390/cancers10120499 · Cited by 57
Niche Cells and Signals that Regulate Lung Alveolar Stem Cells In VivoPreprint
Juul, N. H., Stockman, C. A., & Desai, T. (2020) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a035717 · Cited by 55
“The originally identified and most studied is the AT2 cell (Kapanci et al. 1969; Adamson and Bowden 1974; Barkauskas et al. 2013; Desai et al. 2014), which also plays a critical physiological role in producing surfactant.”
BackgroundShi, Q., Tang, J., Liu, X., & Liu, R. (2021) · Environmental Science Nano · doi:10.1039/d1en00465d · Cited by 54
In vitro model alveoli from photodegradable microsphere templates
Lewis, K. J. R., Tibbitt, M. W., Zhao, Y., Branchfield, K., Sun, X., Balasubramaniam, V., & Anseth, K. S. (2015) · Biomaterials Science · doi:10.1039/c5bm00034c · Cited by 54
β1 Integrin regulates adult lung alveolar epithelial cell inflammation
Plosa, E. J., Benjamin, J. T., Sucre, J. M. S., Gulleman, P. M., Gleaves, L. A., Han, W., Kook, S., Polosukhin, V. V., Haake, S. M., Guttentag, S. H., et al. (2019) · JCI Insight · doi:10.1172/jci.insight.129259 · Cited by 51
Tian, L., Gao, J., Garcia, I. M., Chen, H. J., Castaldi, A., & Chen, Y. (2020) · Wiley Interdisciplinary Reviews Developmental Biology · doi:10.1002/wdev.399 · Cited by 54
“…stem/progenitor cell populations of human embryonic (Nikolic et al., 2017) or adult lung tissue, for example, basal (Butler et al., 2016; Danahay et al., 2015; Hegab et al., 2012; Hild & Jaffe, 2016; Mou et al., 2016; Rock et al., 2009; Sachs et al., 2019) and AT2 cells (Barkauskas et al., 2013).”
BackgroundInfluentialKiener, M., Roldán, N., Machahua, C., Sengupta, A., Geiser, T., Guenat, O. T., Funke-Chambour, M., Hobi, N., & Julio, M. K. (2021) · Frontiers in Medicine · doi:10.3389/fmed.2021.644678 · Cited by 52
“In vitro, isolated human ATII cells behave as facultative stem cells giving rise to alveolar organoids containing multiple cell types (25, 26).”
BackgroundYAP regulates alveolar epithelial cell differentiation and AGER via NFIB/KLF5/NKX2-1
Gokey, J. J., Snowball, J. M., Sridharan, A., Sudha, P., Kitzmiller, J. A., Xu, Y. J., & Whitsett, J. A. (2021) · iScience · doi:10.1016/j.isci.2021.102967 · Cited by 55
Ekanger, C. T., Zhou, F., Bohan, D., Lotsberg, M. L., Ramnefjell, M., Hoareau, L., Røsland, G. V., Lü, N., Aanerud, M., Gärtner, F., et al. (2022) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2022.841447 · Cited by 55
“Under these challenging conditions, AT2 cells have been shown to display stem cell potential and the ability of AT2 cells to self-renew and differentiate into AT1 cells has been shown in several studies (Barkauskas et al., 2013; Desai et al., 2014; Katsura et al., 2019).”
BackgroundProgenitor potential of lung epithelial organoid cells in a transplantation model
Louie, S. M., Moye, A. L., Wong, I. G., Lu, E., Shehaj, A., de Alba, C. G., Ararat, E., Raby, B. A., Lu, B., Paschini, M., et al. (2022) · Cell Reports · doi:10.1016/j.celrep.2022.110662 · Cited by 52
Alysandratos, K., Garcia-de-Alba, C., Yao, C., Pessina, P., Huang, J., Villacorta-Martín, C., Hix, O. T., Minakin, K., Burgess, C. L., Bawa, P., et al. (2022) · JCI Insight · doi:10.1172/jci.insight.158937 · Cited by 54
Self-citationTóth, A., Kannan, P. S., Snowball, J. M., Kofron, M. J., Wayman, J. A., Bridges, J. P., Miraldi, E. R., Swarr, D. T., & Zacharias, W. J. (2023) · Nature Communications · doi:10.1038/s41467-023-44184-0 · Cited by 55
“To address these challenges, we re fi ned and standardized the conditions and inputs of co-culture of murine AT2 cells and alveolar fi broblasts 2,3,14,15 .”
Zhan, J., Wang, P., Niu, M., Wang, Y., Zhu, X., Guo, Y., & Zhang, H. (2014) · Histopathology · doi:10.1111/his.12585 · Cited by 52
“Recent genetic lineage-tracing studies in the mouse demonstrated convincingly that the SFTPC AEC2 population proliferates in vivo and generates AEC1s, indicating that type II pneumocytes are stem cells in the adult lung.(37,39) Interestingly, we found that HoxB9 is highly expressed in some type II pneumocytes (Figure…”
BackgroundLiebler, J. M., Marconett, C. N., Juul, N. H., Wang, H., Liu, Y., Flodby, P., Laird‐Offringa, I. A., Minoo, P., & Zhou, B. (2015) · American Journal of Physiology-Lung Cellular and Molecular Physiology · doi:10.1152/ajplung.00337.2015 · Cited by 52
Differentiation of Club Cells to Alveolar Epithelial Cells In Vitro
Zheng, D., Soh, B.-S., Yin, L., Hu, G., Chen, Q., Choi, H., Han, J., Chow, V. T. K., & Chen, J. (2017) · Scientific Reports · doi:10.1038/srep41661 · Cited by 52
Weeden, C. E., Chen, Y., Ma, S. B., Hu, Y., Ramm, G., Sutherland, K. D., Smyth, G. K., & Asselin-Labat, M.-L. (2017) · PLoS Biology · doi:10.1371/journal.pbio.2000731 · Cited by 53
Liu, Y., Shi, Y., Liu, Y., Pan, X., & Zhang, K. (2018) · Acta Pharmacologica Sinica · doi:10.1038/s41401-018-0007-9 · Cited by 53
Kanagaki, S., Ikeo, S., Suezawa, T., Yamamoto, Y., Seki, M., Hirai, T., Hagiwara, M., Suzuki, Y., & Gotoh, S. (2020) · Stem Cells · doi:10.1002/stem.3302 · Cited by 52
“A mouse alveolar organoid (AO) culture was subsequently reported, demonstrating the differentiation of primary AT2 cells into AT1 cells.(4) In a more recent study, the Wnt-responsible subpopulation of AT2 cells was reported to have the Shuhei Kanagaki and Satoshi Ikeo are co-first authors.”
BackgroundOrganoid: a powerful tool to study lung regeneration and disease
Lu, T., Cao, Y., Zhao, P., Shen, S., & Xi, Y. (2021) · Cell Regeneration · doi:10.1186/s13619-021-00082-8 · Cited by 55
“Mulay et al. employed alveolospheres of FACS sorted distal lung epithelial cells mixed with MRC5 cells and revealed that infection triggers both cell-autonomous and non-cellautonomous apoptosis that may contribute to alveolar injury (Mulay et al., 2020).”
BackgroundInfluentialAnticoagulant Biomimetic Consecutive Gas Exchange Network for Advanced Artificial Lung Membrane
Feng, Y., Wang, Q., Zhi, L., Sun, S., & Zhao, C. (2022) · Journal of Membrane Science · doi:10.1016/j.memsci.2022.120502 · Cited by 52
Sidarta-Oliveira, D., Jara, C. P., Ferruzzi, A. J., Skaf, M. S., Velander, W. H., ARAUJO, E. P. D., & Velloso, L. A. (2020) · Scientific Reports · doi:10.1038/s41598-020-76488-2 · Cited by 54
Sustained amphiregulin expression in intermediate alveolar stem cells drives progressive fibrosis
Zhao, R., Wang, Z., Wang, G., Geng, J., Wu, H., Liu, X., Bin, E., Sui, J., Dai, H., & Tang, N. (2024) · Cell stem cell · doi:10.1016/j.stem.2024.07.004 · Cited by 52
Mitochondrial quality control in alveolar epithelial cells damaged by S. aureus pneumonia in mice
Suliman, H. B., Kraft, B. D., Bartz, R. R., Chen, L., Welty‐Wolf, K. E., & Piantadosi, C. A. (2017) · American Journal of Physiology-Lung Cellular and Molecular Physiology · doi:10.1152/ajplung.00197.2017 · Cited by 52
Successful Establishment of Primary Type II Alveolar Epithelium with 3D Organotypic Coculture
Sucre, J. M. S., Jetter, C. S., Loomans-Kropp, H. A., Williams, J. A., Plosa, E. J., Benjamin, J. T., Young, L. R., Kropski, J. A., Calvi, C. L., Kook, S., et al. (2018) · American Journal of Respiratory Cell and Molecular Biology · doi:10.1165/rcmb.2017-0442ma · Cited by 51
Distal lung epithelial progenitor cell function declines with age
Watson, J. K., Sanders, P. N., Dunmore, R., Rosignoli, G., Julé, Y., Rawlins, E. L., Mustelin, T., May, R. D., Clarke, D. L., & Finch, D. K. (2020) · Scientific Reports · doi:10.1038/s41598-020-66966-y · Cited by 54
The evolution ofin vitromodels of lung fibrosis: promising prospects for drug discovery
Kolanko, E., Cargnoni, A., Papait, A., Silini, A. R., Czekaj, P., & Parolini, O. (2024) · European Respiratory Review · doi:10.1183/16000617.0127-2023 · Cited by 56
Ito, Y., Correll, K. A., Schiel, J. A., Finigan, J. H., Prekeris, R., & Mason, R. J. (2014) · American Journal of Physiology-Lung Cellular and Molecular Physiology · doi:10.1152/ajplung.00233.2013 · Cited by 50
Inhaled resveratrol treatments slow ageing-related degenerative changes in mouse lung
Navarro, S., Reddy, R., Lee, J., Warburton, D., & Driscoll, B. (2017) · Thorax · doi:10.1136/thoraxjnl-2016-208964 · Cited by 50
Dinh, P., Cores, J., Hensley, M. T., Vandergriff, A. C., Tang, J., Allen, T. A., Caranasos, T. G., Adler, K. B., Lobo, L. J., & Cheng, K. (2017) · Respiratory Research · doi:10.1186/s12931-017-0611-0 · Cited by 49
“club cells are responsible for maintaining the bronchiolar epithelium [8, 9].”
BackgroundFaber, S. C., & McCullough, S. D. (2018) · Applied In Vitro Toxicology · doi:10.1089/aivt.2018.0002 · Cited by 57
“When cultured under appropriate ALI conditions, airway basal epithelial cells self-organize into tracheospheres or bronchospheres, whereas primary alveolar cells become alveolospheres; however, it remains to be determined whether airway-derived organoids contain normal basal cells or multipotent committed progenitor c…”
BackgroundSchruf, E., Schroeder, V., Le, H. Q., Schönberger, T., Raedel, D., Stewart, E. L., Fundel‐Clemens, K., Bluhmki, T., Weigle, S., Schuler, M. J., et al. (2020) · The FASEB Journal · doi:10.1096/fj.201902926r · Cited by 50
Song, S., Liu, B., Habibie, H., van den Bor, J., Smit, M. J., Gosens, R., Wu, X., Brandsma, C., Cool, R. H., Haisma, H. J., et al. (2021) · EBioMedicine · doi:10.1016/j.ebiom.2021.103412 · Cited by 50
“For example, basal cells in the distal airway and alveolar type II (ATII) cells in alveoli [5,6] have repair and renewal capacities [7].”
A bird’s eye view of fibroblast heterogeneity: A pan‐disease, pan‐cancer perspective
Pradhan, R., Krishnamurty, A. T., Fletcher, A. L., Turley, S. J., & Müller, S. (2021) · Immunological Reviews · doi:10.1111/imr.12990 · Cited by 51
Basal epithelial stem cells cross an alarmin checkpoint for postviral lung disease
Wu, K., Kamimoto, K., Zhang, Y., Yang, K., Keeler, S. P., Gerovac, B. J., Agapov, E. V., Austin, S. R., Yantis, J., Gissy, K. A., et al. (2021) · Journal of Clinical Investigation · doi:10.1172/jci149336 · Cited by 50
“Here, we examined the SeV model to address each of these issues and found that (a) subsets of both basal and AT2 cells were activated for long-term hyperplasia after viral infection; (b) the activated basal cell lineage was not traced into AT2 cells, perhaps consistent with studies of lung development and injury that…”
MethodRepairing the lungs one breath at a time: How dedicated or facultative are you?Preprint
Leach, J. P., & Morrisey, E. E. (2018) · Genes & Development · doi:10.1101/gad.319418.118 · Cited by 52
“The ability of AT2 cells to self-renew and differentiate into AT1 cells was first described in the early 1970s (Evans et al. 1973, 1975) and was further characterized more recently through lineage tracing studies (Barkauskas et al. 2013).”
BackgroundChanda, D., Rehan, M., Smith, S. R., Dsouza, K. G., Wang, Y., Bernard, K. F., Kurundkar, D., Memula, V., Kojima, K., Mobley, J. A., et al. (2021) · eLife · doi:10.7554/elife.68049 · Cited by 50
“Type 2 alveolar epithelial cells (AEC2s) serve as facultative stem/progenitor cells in adult mammalian lungs and differentiate into type 1 alveolar epithelial cells (AEC1s) in response to diverse injuries to reconstitute and reestablish the alveolar gas exchange surface (Barkauskas et al., 2013).”
BackgroundMethodLee, H., Lee, J.-Y., Hong, S., Rahman, I., & Yang, S. (2018) · Frontiers in Pharmacology · doi:10.3389/fphar.2018.00684 · Cited by 49
“The type II cells comprise only 4% of the alveolar surface area, yet they display a multifunctional pneumocyte including synthesis and secretion of surfactant, xenobiotic metabolism, transepithelial movement of water, progenitor cells capable of self-renewal and differentiation into type I pneumocyte for regeneration…”
BackgroundLi, C., Lee, M. K., Gao, F., Webster, S., Di, H., Duan, J., Yang, C.-Y., Bhopal, N., Peinado, N., Pryhuber, G., et al. (2019) · Development · doi:10.1242/dev.176354 · Cited by 49
“In 3D organoid cultures, unfractionated PDGFRa cells are known to exhibit unique properties in supporting and promoting adult AT2 cell proliferation and differentiation (Barkauskas et al., 2013).”
BackgroundHagan, A. S., Zhang, B., & Ornitz, D. M. (2019) · Development · doi:10.1242/dev.181032 · Cited by 49
“ALFs are interstitial lipid laden cells that secrete triglycerides, store retinoids and provide trophic support for alveolar type 2 cells (Barkauskas et al., 2013;McGowan et al., 1995; Torday et al., 1995).”
BackgroundLung epithelium damage in COPD – An unstoppable pathological event?
Hadžić, S., Wu, C., Avdeev, S. N., Weißmann, N., SCHERMULY, R. T., & Kosanovic, D. (2020) · Cellular Signalling · doi:10.1016/j.cellsig.2020.109540 · Cited by 53
Riccetti, M., Gokey, J. J., Aronow, B. J., & Perl, A. T. (2020) · Matrix Biology · doi:10.1016/j.matbio.2020.05.002 · Cited by 50
“A mixed population of dim and bright Pdgfra-GFP + fibroblasts support alveolar organoid formation and epithelial differentiation, while Pdgfraneg lung fibroblasts supported bronchiolar organoids and epithelial differentiation [65].”
BackgroundSenescence in Pulmonary Fibrosis: Between Aging and Exposure
Venosa, A. (2020) · Frontiers in Medicine · doi:10.3389/fmed.2020.606462 · Cited by 51
de Carvalho, A. L. R. T., Liu, H., Chen, Y., Porotto, M., Moscona, A., & Snoeck, H. (2021) · Nature Protocols · doi:10.1038/s41596-020-00476-z · Cited by 49
Ahmadvand, N., Khosravi, F., Lingampally, A., Wasnick, R. M., Vazquez‐Armendariz, A. I., Carraro, G., Heiner, M., Rivetti, S., Lv, Y., Wilhelm, J., et al. (2021) · European Respiratory Journal · doi:10.1183/13993003.04168-2020 · Cited by 49
“The identity of these survivor cells, however, is not clear [3].”
Ke, R., Zitzmann, C., Ribeiro, R. M., & Perelson, A. S. (2020) · medRxiv · doi:10.1101/2020.09.25.20201772 · Cited by 51
“Further, regeneration of target cells by proliferation may become significant especially in the LRT (19, 39) and we consider a model later that incorporates proliferation in the LRT (see below) as virus in the URT has declined to undetectable or almost undetectable levels by this time (Fig.”
Therapeutic strategies to target connective tissue growth factor in fibrotic lung diseases
Isshiki, T., Naiel, S., Vierhout, M., Otsubo, K., Ali, P., Tsubouchi, K., Yazdanshenas, P., Kumaran, V. R., Dvorkin‐Gheva, A., Kolb, M. R. J., et al. (2023) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2023.108578 · Cited by 49
Activation of Type II Cells into Regenerative Stem Cell Antigen-1+ Cells during Alveolar Repair
Liu, Y., Kumar, V. S., Zhang, W., Rehman, J., & Malik, A. B. (2014) · American Journal of Respiratory Cell and Molecular Biology · doi:10.1165/rcmb.2013-0497oc · Cited by 48
Wagner, D. E., Cardoso, W. V., Gilpin, S. E., Majka, S. M., Ott, H. C., Randell, S. H., Thébaud, B., Waddell, T. K., & Weiss, D. J. (2016) · Annals of the American Thoracic Society · doi:10.1513/annalsats.201606-466st · Cited by 49
Self-citationDai, Y.-B., Miao, Y., Wu, W.-F., Li, Y., D’Errico, F., Su, W., Burns, A. R., Huang, B., Maneix, L., Warner, M. N., et al. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1607590113 · Cited by 48
Ota, C., Ng-Blichfeldt, J.-P., Korfei, M., Alsafadi, H. N., Lehmann, M., Skrońska-Wąsek, W., Santis, M. M. D., Günther, A., Wagner, D. E., & Königshoff, M. (2018) · Scientific Reports · doi:10.1038/s41598-018-31214-x · Cited by 49
Platform Effects on Regeneration by Pulmonary Basal Cells as Evaluated by Single-Cell RNA Sequencing
Greaney, A. M., Adams, T. S., Raredon, M. S. B., Gubbins, E., Schupp, J. C., Engler, A. J., Ghaedi, M., Yuan, Y., Kaminski, N., & Niklason, L. E. (2020) · Cell Reports · doi:10.1016/j.celrep.2020.03.004 · Cited by 49
“Engineered lung uniquely gained a population defined by Hopx expression (Figures 4D and S6C), a marker typically associated with ATI cells (Barkauskas et al., 2013) and involved in the regulation of pulmonary maturation (Yin et al., 2006), although it has also been found to be upregulated in early…”
Kunisaki, S. M., Jiang, G., Biancotti, J. C., Ho, K. K. Y., Dye, B. R., Liu, A. P., & Spence, J. R. (2020) · Stem Cells Translational Medicine · doi:10.1002/sctm.20-0199 · Cited by 48
“In contrast, type II pneumocytes serve as alveolar stem cells and secrete pulmonary surfactant.(53) The increased expression of VIM”
BackgroundOrganoid models: assessing lung cell fate decisions and disease responses
Liberti, D. C., & Morrisey, E. E. (2021) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2021.09.008 · Cited by 45
Telomere Dysfunction in Idiopathic Pulmonary Fibrosis
Zhang, K., Xu, L., & Cong, Y. (2021) · Frontiers in Medicine · doi:10.3389/fmed.2021.739810 · Cited by 51
NF-κB drives epithelial-mesenchymal mechanisms of lung fibrosis in a translational lung cell model
Sieber, P., Schäfer, A., Lieberherr, R., Caimi, S. L., Lüthi, U., Ryge, J., Bergmann, J. H., Goff, F. L., Stritt, M., Blattmann, P., et al. (2022) · JCI Insight · doi:10.1172/jci.insight.154719 · Cited by 45
“However, when EC were used in 3D cocultures, they seemed to dampen and not promote the activation of cocultured FB (10, 12, 16).”
Weiner, A. I., Zhao, G., Zayas, H. M., Holcomb, N. P., Adams‐Tzivelekidis, S., Wong, J., Gentile, M. E., Reddy, D., Wei, J., Palashikar, G., et al. (2022) · Cell Reports · doi:10.1016/j.celrep.2022.111805 · Cited by 45
““euplastic”) regeneration, during which they proliferate and differentiate into AT1s (Barkauskas et al., 2013; Evans et al., 1973; Kathiriya et al., 2020; Kim et al., 2005; Liu et al., 2019), restoring both the surfactant production and gas-exchanging alveolar epithelium.”
BackgroundInfluentialModeling human lung development and disease using pluripotent stem cells
Snoeck, H. (2014) · Development · doi:10.1242/dev.115469 · Cited by 48
Alveologenesis: key cellular players and fibroblast growth factor 10 signaling
Chao, C., Moiseenko, A., Zimmer, K., & Bellusci, S. (2016) · Molecular and Cellular Pediatrics · doi:10.1186/s40348-016-0045-7 · Cited by 47
“Pdgfra+ cells/LIF constitute a stem cell niche for AEC II stem cells [34].”
BackgroundDye, B. R., Miller, A. J., & Spence, J. R. (2016) · Current Pathobiology Reports · doi:10.1007/s40139-016-0102-x · Cited by 46
Barr, J., Gentile, M. E., Lee, S., Kotas, M. E., Costa, M., Holcomb, N. P., Jaquish, A. A., Palashikar, G., Soewignjo, M., McDaniel, M. M., et al. (2022) · eLife · doi:10.7554/elife.78074 · Cited by 46
Mia, M. M., & Singh, M. K. (2022) · FEBS Journal · doi:10.1111/febs.16449 · Cited by 50
Alveolar regeneration by airway secretory-cell-derived p63+ progenitors
Lv, Z., Liu, Z., Liu, K., Lin, X., Pu, W., Li, Y., Zhao, H., Xi, Y., Sui, P., Vaughan, A. E., et al. (2024) · Cell stem cell · doi:10.1016/j.stem.2024.08.005 · Cited by 47
Dorr, C. R., Janik, C. L., Weg, M. T., Been, R. A., Bader, J. M., Kang, R. J. D., Ng, B., Foran, L. A., Landman, S. R., O’Sullivan, M. G., et al. (2015) · Molecular Cancer Research · doi:10.1158/1541-7786.mcr-14-0674-t · Cited by 46
“In previous screens using the same approach in the intestines and the liver, tumor latency was shorter than that in our study, which could be related to a slower turnover rate and lower absolute numbers of cells being targeted using the Spc promoter (43).”
BackgroundChung, E. J., McKay-Corkum, G. B., Chung, S. I., White, A. O., Scroggins, B. T., Mitchell, J. B., Mulligan‐Kehoe, M. J., & Citrin, D. E. (2015) · International Journal of Radiation Oncology*Biology*Physics · doi:10.1016/j.ijrobp.2015.11.044 · Cited by 46
“AECII function as the alveolar stem cell, giving rise to AECII and type I pneumocytes after toxic insults (7,47,48).”
Alveolar injury and regeneration following deletion of ABCA3
Rindler, T. N., Stockman, C. A., Filuta, A. L., Brown, K. M., Snowball, J. M., Zhou, W., Veldhuizen, R. A. W., Zink, E., Dautel, S. E., Clair, G., et al. (2017) · JCI Insight · doi:10.1172/jci.insight.97381 · Cited by 46
“To identify the role of Abca3 in postnatal lungs, transgenic Sftpc-CreERT2, Abca3flox/flox (Sftpc-CreERT2;Abca3flox/flox) (18) mice were produced, hereafter termed control.”
BackgroundHung, C. F., Wilson, C. L., & Schnapp, L. M. (2019) · Advances in experimental medicine and biology · doi:10.1007/978-3-030-11093-2_3 · Cited by 46
Alveolar Epithelial Type 2 Cell Dysfunction in Idiopathic Pulmonary Fibrosis
Zhu, W., Tan, C., & Zhang, J. (2022) · Lung · doi:10.1007/s00408-022-00571-w · Cited by 50
Niethamer, T. K., Planer, J. D., Morley, M. P., Babu, A., Zhao, G., Basil, M. C., Cantu, E., Frank, D. B., Diamond, J. M., Nottingham, A. N., et al. (2025) · Cell stem cell · doi:10.1016/j.stem.2024.12.002 · Cited by 47
Blom, R. A. M., Erni, S. T., Krempaská, K., Schaerer, O., van Dijk, R. M., Amacker, M., Moser, C., Hall, S. R. R., von Garnier, C., & Blank, F. (2016) · PLoS ONE · doi:10.1371/journal.pone.0163539 · Cited by 48
“EpCAM cells are primary epithelial progenitor cells located in small airways [49] and were employed as a comparison to PHNECs that are also primary cells, but originate from larger airways and 16HBE, representing a cell line.”
BackgroundTan, Q., Ma, X. Y., Liu, W. Y., Meridew, J. A., Jones, D. L., Haak, A. J., Sicard, D., Ligresti, G., & Tschumperlin, D. J. (2019) · American Journal of Respiratory Cell and Molecular Biology · doi:10.1165/rcmb.2018-0390oc · Cited by 45
Epithelial cell plasticity defines heterogeneity in lung cancer
Sarode, P., Mansouri, S., Karger, A., Schaefer, M. B., Grimminger, F., Seeger, W., & Savai, R. (2019) · Cellular Signalling · doi:10.1016/j.cellsig.2019.109463 · Cited by 45
Zhang, K., Yao, E., Lin, C., Chou, Y., Wong, J., Li, J., Wolters, P. J., & Chuang, P. (2020) · eLife · doi:10.7554/elife.53688 · Cited by 45
“Alveolosphere assays were performed as previously described (Barkauskas et al., 2013) with minor modifications.”
MethodMock, J. R., Dial, C. F., Tune, M. K., Gilmore, R. C., O’Neal, W. K., Dang, H., & Doerschuk, C. M. (2020) · American Journal of Respiratory Cell and Molecular Biology · doi:10.1165/rcmb.2019-0399oc · Cited by 50
Stem cells in pulmonary alveolar regeneration
Wu, H., & Tang, N. (2021) · Development · doi:10.1242/dev.193458 · Cited by 44
“Combined with genetic manipulations, diphtheria toxin is often expressed in a cell-specific manner to induce the selective ablation of a targeted cell type (Barkauskas et al., 2013; Mitamura et al., 1995; Murphy, 1996).”
BackgroundInfluentialVianello, A., Guarnieri, G., Braccioni, F., Lococo, S., Molena, B., Cecchetto, A., Giraudo, C., Marchi, L. B. D., Caminati, M., & Senna, G. (2021) · Clinical Chemistry and Laboratory Medicine (CCLM) · doi:10.1515/cclm-2021-1021 · Cited by 45
“Despite the fact that multiple cell types may become infected, the infection and death of type II alveolar epithelial cells (AEC) seem to be of critical importance as they stabilize and repair the epithelial barrier, secrete vital prosurfactant and are not efficiently replaced [44, 45].”
BackgroundHeterogeneous groups of alveolar type II cells in lung homeostasis and repair
Chen, Q., & Liu, Y. (2020) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00341.2020 · Cited by 50
“Importantly, AT2 also 49 act as adult tissue stem cells in lung homeostatic maintenance, repair and regeneration(2, 10, 11).”
BackgroundInfluentialCellular and Molecular Mechanisms in Idiopathic Pulmonary Fibrosis
Zhang, Y., & Wang, J. (2023) · Advances in respiratory medicine · doi:10.3390/arm91010005 · Cited by 47
“After alveolar epithelial cell damage, AT2 cells can rapidly proliferate and differentiate into AT1 cells, thereby maintaining the integrity of alveolar epithelial cells, which is necessary for maintaining alveolar homeostasis and promoting alveolar regeneration [31].”
BackgroundOrganogenesis of adult lung in a dish: Differentiation, disease and therapy
Choi, J., Iich, E., & Lee, J. (2016) · Developmental Biology · doi:10.1016/j.ydbio.2016.10.002 · Cited by 44
“However, no cells morphologically resembling or expressing AT1 markers were detected in these spheres (Barkauskas et al., 2013).”
BackgroundMethodInfluentialPaul, A., Krelin, Y., Arif, T., Jeger, R. E., & Shoshan‐Barmatz, V. (2017) · Molecular Therapy · doi:10.1016/j.ymthe.2017.12.020 · Cited by 44
Gupta, R., Charron, J. G., Stenger, C. L., Painter, J., Steward, H., Cook, T. W., Faber, W., Frisch, A., Lind, E., Bauss, J. M., et al. (2020) · Journal of Biological Chemistry · doi:10.1074/jbc.ra120.014873 · Cited by 48
“In the lung, ACE2 is expressed in the type 2 pneumocytes, putative progenitor cells of alveolar epithelia linked to lung fibrosis pathways (18, 19).”
A cell‐centric view of lung alveologenesis
Ellis, L. V., & Chen, J. (2020) · Developmental Dynamics · doi:10.1002/dvdy.271 · Cited by 45
“Besides producing surfactants, AT2 cells function as facultative stem cells, self-renewing and differentiating into AT1 cells during injury-repair in the adult lung.(11,24) Conceptually possible and traditionally believed, AT2 cells could also give rise to AT1 cells during development and in turn contribute to the alv…”
BackgroundLung organoids: advances in generation and 3D-visualization
Cunniff, B., Druso, J. E., & van der Velden, J. L. J. (2021) · Histochemistry and Cell Biology · doi:10.1007/s00418-020-01955-w · Cited by 45
Evolution of organoid technology: Lessons learnt in Co-Culture systems from developmental biology
Zahmatkesh, E., Rad, N. K., Mirzaei, H., Shpichka, A. I., Timashev, P. S., Mahmoudi, T., & Vosough, M. (2021) · Developmental Biology · doi:10.1016/j.ydbio.2021.03.001 · Cited by 46
Studying SARS-CoV-2 infectivity and therapeutic responses with complex organoids
Chen, K. G., Park, K., & Spence, J. R. (2021) · Nature Cell Biology · doi:10.1038/s41556-021-00721-x · Cited by 45
Valyaeva, A. A., Zharikova, A. A., Kasianov, A. S., Vassetzky, Y. S., & Sheval, E. V. (2020) · Scientific Reports · doi:10.1038/s41598-020-74598-5 · Cited by 46
Loss of E-cadherin is causal to pathologic changes in chronic lung disease
Ghosh, B., Loube, J., Thapa, S., Ryan, H., Capodanno, E., Chen, D., Swaby, C., Chen, S., Mahmud, S., Girgis, M., et al. (2022) · Communications Biology · doi:10.1038/s42003-022-04150-w · Cited by 43
Cell-based therapy in lung regenerative medicine
Yang, J., & Jia, Z. (2014) · Regenerative Medicine Research · doi:10.1186/2050-490x-2-7 · Cited by 43
Yamada, M., Fujino, N., & Ichinose, M. (2016) · Inflammation and Regeneration · doi:10.1186/s41232-016-0020-7 · Cited by 45
“Some alveolar type II cells can differentiate into alveolar type I cells (AT I cells) for homeostasis and after injury [47, 48].”
Gouveia, L., Betsholtz, C., & Andræ, J. (2017) · Physiological Reports · doi:10.14814/phy2.13092 · Cited by 42
“The PdgfalacZ expression in AEC2s is of note, as AEC2s have been described as stem cells in the adult lung (Barkauskas et al. 2013).”
BackgroundInfluentialChen, Y., Feng, J., Zhao, S., Han, L. K., Yang, H., Lin, Y., & Rong, Z. (2018) · Stem Cells and Development · doi:10.1089/scd.2018.0042 · Cited by 42
“…cell types, cuboidal alveolar type 2 (AT2) cells that secrete surfactant to prevent alveolar collapse and function as stem cells to regenerate alveolar type 1 (AT1) cells during damage repair and squamous AT1 cells that cover most of the surface area of the alveoli and mediate gas exchange [1,2].”
A transitional stem cell state in the lung
Verheyden, J. M., & Sun, X. (2020) · Nature Cell Biology · doi:10.1038/s41556-020-0561-5 · Cited by 41
The role of macrophage-derived TGF-β1 on SiO 2 -induced pulmonary fibrosis: A review
Zhang, Z., Tian, H.-T., Hu, L., & Xie, R. (2021) · Toxicology and Industrial Health · doi:10.1177/0748233721989896 · Cited by 47
“AT II in adult tissues include epithelial stem cells (Barkauskas et al., 2013; Liu et al., 2015), and AT I include terminally differentiated cells (Gonzalez et al.”
BackgroundLv, X., Liu, C., Liu, S., Li, Y., Wang, W., Li, K., Hua, F., Cui, B., Zhang, X., Yu, J., et al. (2021) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2021.07.015 · Cited by 48
Bluhmki, T., Traub, S., Müller, A.-K., Groetzner, S., Schruf, E., Bammert, M., Leist, M., Gantner, F., Garnett, J. P., & Heilker, R. (2021) · Scientific Reports · doi:10.1038/s41598-021-96565-4 · Cited by 44
COVID-19 lung disease shares driver AT2 cytopathic features with Idiopathic pulmonary fibrosis
Sinha, S., Castillo, V., Espinoza, C. R., Tindle, C., Fonseca, A. G., Dan, J. M., Katkar, G. D., Das, S., Sahoo, D., & Ghosh, P. (2022) · EBioMedicine · doi:10.1016/j.ebiom.2022.104185 · Cited by 46
Conceptual Approaches to Lung Injury and Repair
Zemans, R. L., Henson, P. M., Henson, J. E., & Janssen, W. J. (2015) · Annals of the American Thoracic Society · doi:10.1513/annalsats.201408-402mg · Cited by 42
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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