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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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“Although studies have shown that multiple types of lung stem progenitor cells can mediate the r egenerative repair of lung tissue after the onset of ALI [6], AT2 cells are the main stem and progenitor cells involved in the regeneration and repair of damaged lung tissue [7].”
InfluentialWang, H., Gao, N., Wang, L., Yang, F., Liu, B., Hu, X., Zhao, Y., Sha, R., Li, X., & Li, H. (2025) · Cancer Treatment Reviews · doi:10.1016/j.ctrv.2025.103044 · Cited by 15
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“AT2 cells serve as the facultative adult stem cells of the distal lung, and they are responsible for regenerating the alveoli through self-renewal and differentiation into AT1 cells [2–4].”
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“53 DATPs, 52 known as pre-AT1 transitional cell state (PATS) 54 or alveolar differentiation intermediate (ADI), 55 have been recently identi fi ed as a transitional cell state of AT2 cells toward into AT1 cells in regenerating alveolar tissues, linked to impaired alveolar regeneration and lung fi…”
BackgroundTRIOBP modulates β-catenin signaling by regulation of miR-29b in idiopathic pulmonary fibrosis
Wang, L., Zhao, W., Xia, C., Ma, S., Li, Z., Wang, N., Ding, L., Wang, Y., Cheng, L. C., Liu, H., et al. (2023) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-023-05080-4 · Cited by 15
“Alveolar epithelial type II cells (AECIIs) can serve as progenitor cells that preserve the homeostasis of the epithelium and restore damaged epithelium following injury [7–9].”
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Self-citationReinitiating lung development: a novel approach in the management of bronchopulmonary dysplasia
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“Both cell types transport ions (8, 11, 19), perform immunomodulatory functions (36, 37), and act as progenitor cells following injury (2, 14, 18).”
BackgroundCell-Based Therapeutic Approaches for Cystic Fibrosis
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“Despite the fact that LIFs were initially believed to only assist AT2 cells in surfactant production during neonatal life, recent studies have shown that these cells are important for selfrenewal and differentiation of AT2 stem cells during adulthood (Barkauskas et al., 2013).”
Nouri-Keshtkar, M., Taghizadeh, S., Farhadi, A., Ezaddoustdar, A., Vesali, S., Hosseini, R., Totonchi, M., Kouhkan, A., Chen, C., Zhang, J., et al. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.676150 · Cited by 14
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InfluentialSingle-cell RNA sequencing profiling of the effects of aging on alveolar stem cells
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“Since type II pneumocytes are considered as the stem cells or progenitors in alveoli (32), SARS-CoV-2 infection-induced massive alveolar epithelial cell death may lead to abnormal regeneration of type II pneumocytes for repair along with the production of CEA, which was similar to the uncontrolled proliferation of lun…”
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“Within the alveolar epithelium, constituted of alveolar type I epithelial (ATI) and ATII cells, ATII cells are considered self-renewing stem cells that also regenerate ATI cells after injury (3).”
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“…CEACAM6 expression in type II cells, which can differentiate into type I cells during development and repair from injury (Kapanci et al. 1969; Barkauskas et al. 2013), we crossed CEABAC mice with CBG transgenic mice: the CBG mouse (SPC-BAC-EGFP) contains a mouse BAC modified to express EGFP…”
MethodRevisiting mTOR and Epithelial–Mesenchymal Transition
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“The alveolar epithelium is composed of flat type 1 cells (AT1), which are in close proximity to capillaries and mediate gas exchange, and cuboidal type 2 cells (AT2), which regulate surfactant production and secretion (1).”
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“…human lung mesenchyme drives human AEC2 transdifferentiation into KRT5+ basal cells in vitro Previously reported hAEC2 organoids have utilized MRC5, a fetal human lung fibroblasts cell line, as feeders to maintain hAEC2s in vitro (Barkauskas et al., 2013; Li et al., 2020; Zacharias et al., 2018).”
Definition and Signatures of Lung Fibroblast Populations in Development and Fibrosis in Mice and MenPreprint
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Self-citationAging and Susceptibility to Pulmonary Disease
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“AT2 cells serve as primary progenitors of the alveolar epithelium, both self-renewing and giving rise to AT1 cells to restore the alveolar epithelium during normal maintenance and repair following lung injury [3,4].”
BackgroundInfluentialWnt5a/β-catenin axis is involved in the downregulation of AT2 lineage by PAI-1
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“Subsequently, EpCAM (CD326)+ epithelial progenitors were isolated from this unfractionated cell suspensions from 3 non-IPF and 4 IPF donor (tissue from 1 non-IPF donor did not yield sufficient cell numbers) by negative selection for CD31 and CD45 to deplete endothelial cells and hematopoietic cells (8), followed by a…”
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“A previous study suggested that baicalein induces apoptosis in human lung fibroblasts [39], which is essential for the growth and differentiation of type 2 alveolar epithelial cells [40], which are necessary for normal lung repair [41].”
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“In addition, highly purified AEC IIs have been reported to be incapable of proliferating [36, 39] in vitro and spontaneously differentiating into AEC Is [36, 40–44].”
Mitigating Coronavirus-Induced Acute Respiratory Distress Syndrome by Radiotherapy
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“Under conditions of repairing cellular loss or lung function deficiency, the alveolar cells are able to self-renew and proliferate to restore normal alveolar structure and gas exchange function, which are regulated via an integrated network of mesenchymal, endothelial, and epithelial cells and other components (Barkau…”
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“Recent discoveries suggest that a subpopulation of AT2 has a higher capacity for self-renewal, and the ability to differentiate to AT1 cells during homeostasis and injury (Barkauskas et al., 2013; Zacharias et al., 2018).”
BackgroundReparation of an Inflamed Air-Liquid Interface Cultured A549 Cells with Nebulized Nanocurcumin
Altube, M. J., Caimi, L. I., Huck‐Iriart, C., Morilla, M. J., & Romero, E. L. (2021) · Pharmaceutics · doi:10.3390/pharmaceutics13091331 · Cited by 13
Modeling Human Organ Development and Diseases With Fetal Tissue–Derived Organoids
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Emergency back-up for lung repair
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“epithelial cell II (AECII) stem cell niche in the adult mouse lung [34].”
BackgroundHypercapnia Regulates Gene Expression and Tissue Function
Shigemura, M., Welch, L. C., & Sznajder, J. I. (2020) · Frontiers in Physiology · doi:10.3389/fphys.2020.598122 · Cited by 13
“Alveolar epithelial cells play a role in the response to lung injury and in lung repair (Berthiaume et al., 1999; Barkauskas et al., 2013).”
BackgroundStable Long-Term Culture of Human Distal Airway Stem Cells for Transplantation
Zhou, Y., Wang, Y., Li, D., Zhang, T., Ma, Y., & Zuo, W. (2021) · Stem Cells International · doi:10.1155/2021/9974635 · Cited by 13
Restored alveolar epithelial differentiation and reversed human lung fibrosis upon Notch inhibitionPreprint
Wasnick, R. M., Korfei, M., Piskulak, K., Henneke, I., Wilhelm, J., Mahavadi, P., von der Beck, D., Koch, M., Shalashova, I., Klymenko, O., et al. (2019) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/580498 · Cited by 13
Mesenchymal cells, immune cells and the lung stem cell niche
Thorley, A. J., & Rock, J. R. (2021) · European Respiratory Society eBooks · doi:10.1183/2312508x.10009620 · Cited by 12
Role of airway epithelial cell miRNAs in asthma
Boateng, E., Kovacevic, D., Oldenburg, V., Rådinger, M., & Krauss‐Etschmann, S. (2022) · Frontiers in Allergy · doi:10.3389/falgy.2022.962693 · Cited by 12
“The type II cells differentiate into type I cells in response to injury repair (43, 44).”
BackgroundRegenerative medicine: current research and perspective in pediatric surgery
Deguchi, K., Zambaiti, E., & Coppi, P. D. (2023) · Pediatric Surgery International · doi:10.1007/s00383-023-05438-6 · Cited by 12
“In the alveolar region, alveolar type 2 (AT2) surfactant-producing cells are widely recognised as the best progenitor candidate [34–36].”
BackgroundLiu, K., Tang, M., Xu, W., Meng, X., Jin, H., Han, M., Pu, J., Li, Y., Jiao, F., Sun, R., et al. (2023) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2207210120 · Cited by 12
Kizawa, R., Araya, J., & Fujita, Y. (2023) · Inflammation and Regeneration · doi:10.1186/s41232-023-00295-1 · Cited by 15
“During normal turnover and tissue regeneration, important processes are the proliferation of AT2 cells and their differentiation into AT1 cells [39].”
BackgroundSun, J., Zhang, H., Liu, D., Liu, W., Du, J., Wen, D., Li, L., Zhang, A., Jiang, J., & Zeng, L. (2023) · Respiratory Research · doi:10.1186/s12931-023-02512-4 · Cited by 12
“However, AEC2s are crucial cells in the maintenance of pulmonary homeostasis and regenerate after injury by proliferating and differentiating AEC1s in alveoli [7, 8].”
BackgroundZhao, X., Xiao, H., Li, X., Zhu, L., Peng, Y., Chen, H., Chen, L., Xu, D., & Wang, H. (2024) · Archives of Toxicology · doi:10.1007/s00204-024-03707-4 · Cited by 11
“…the expression of critical developmental and functional marker genes in six fetal major organs, which were selected according to the literature (Barkauskas et al. 2013; Guo et al. 2021; Komori 2020; Li et al. 2022b; Lu et al. 2020; Marini et al. 2017; Miller 2017; Song et al. 2017; Tsukiji et…”
Banaschewski, B. J. H., Michki, S. N., Sitaraman, S., Pan, R., Wang, J. Y., Stewart, D., Goldy, M. K., Lin, S. M., Cantu, E., Katzen, J. B., et al. (2025) · Communications Biology · doi:10.1038/s42003-025-07589-9 · Cited by 12
“Cells were co-cultured at a ratio of 5 000 AT2s:50 000 fi broblasts in MTEC Plus media as previously described for 21 days 82 .”
Huo, C., Jia, Q., Jiao, X., Jiang, Q., Zeng, X., Zhang, J., Wang, Y., Zhu, Z., & Tian, L. (2025) · Journal of Hazardous Materials · doi:10.1016/j.jhazmat.2025.138238 · Cited by 12
Hypertensive urgencies and emergencies: Misconceptions and pitfalls
Angeli, F., Reboldi, G., & Verdecchia, P. (2019) · European Journal of Internal Medicine · doi:10.1016/j.ejim.2019.10.031 · Cited by 12
Mark1 regulates distal airspace expansion through type I pneumocyte flattening in lung development
Fumoto, K., Takigawa-Imamura, H., Sumiyama, K., Yoshimura, S. H., Maehara, N., & Kikuchi, A. (2019) · Journal of Cell Science · doi:10.1242/jcs.235556 · Cited by 11
“, 2002), and alveolar organoids from the adult lung grow and differentiate when co-cultured with Pdgfrα cells (Barkauskas et al., 2013).”
BackgroundTranscriptional responses to injury of regenerative lung alveolar epithelium
Ali, M. S., LaCanna, R., Lian, Z., Huang, J. Y., Tan, Y., Shao, W., Yu, X., & Tian, Y. (2022) · iScience · doi:10.1016/j.isci.2022.104843 · Cited by 12
“Adult AT2 cells exhibit cell cycle re-entry and proliferate to replace lost tissue upon acute lung injury (Barkauskas et al., 2013).”
BackgroundChristenson, J. L., Williams, M. M., & Richer, J. K. (2022) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00181.2022 · Cited by 12
Fujimura, T., Enomoto, Y., Katsura, H., Ogawa, T., Baba, S., Ogata, A., Yamaoka, A., Shiroguchi, K., & Morimoto, M. (2023) · Stem Cells · doi:10.1093/stmcls/sxad044 · Cited by 12
Piao, Y., Yun, S. Y., Fu, Z., Jang, J. M., Back, M. J., Kim, H. H., & Kim, D. K. (2023) · Molecules and Cells · doi:10.14348/molcells.2023.0097 · Cited by 13
“Human alveolar epithelial type 2 cells (HAEC2), which may be the progenitors of type 1 cells (HAEC1), show senescence in COPD (Barkauskas et al., 2013), are capable of self-renewal, and normally become activated by hyperoxic injury or damage to HAEC1 resulting in re-epithelialization of the lung…”
Behavioral Heterogeneity of Adult Mouse Lung Epithelial Progenitor Cells
Chernaya, O., Shinin, V., Liu, Y., & Minshall, R. D. (2014) · Stem Cells and Development · doi:10.1089/scd.2013.0631 · Cited by 12
“Reduced SPC expression was observed in a candidate distal lung a6b4 integrin-expressing stem cell population [6], however, a more recent study indicated that fully differentiated SPC-expressing distal lung cells can also function as stem cells in vivo [30].”
Keratin14 mRNA expression in human pneumocytes during quiescence, repair and disease
Confalonieri, M., Buratti, E., Grassi, G., Bussani, R., Chilosi, M., Farra, R., Abrami, M., Stuani, C., Salton, F., Ficial, M., et al. (2017) · PLoS ONE · doi:10.1371/journal.pone.0172130 · Cited by 12
Seiler, C. L., Song, J. M., Fernandez, J. A., Abrahante, J. E., Kono, T. J. Y., Chen, Y., Ren, Y., Kassie, F., & Tretyakova, N. Y. (2019) · Chemical Research in Toxicology · doi:10.1021/acs.chemrestox.9b00015 · Cited by 12
Wang, Y., Lu, Y. C., Wu, Y., Sun, Y., Zhou, Y., Ma, Q., Zheng, Y., Yu, Q., Cao, Y., Chen, G., et al. (2019) · Stem Cells International · doi:10.1155/2019/7123078 · Cited by 12
Chu, X., Chen, C., Chen, C., Zhang, J., Bellusci, S., & Li, X. (2019) · Frontiers of Medicine · doi:10.1007/s11684-019-0717-5 · Cited by 12
“In the respiratory airway, these cells include the alveolar type 2 (AT2) cells [16, 17] , the alveolar type 1 (AT1) cells [18, 19] , the bronchoalveolar stem cells (BASCs) [20] , and the lineage negative epithelial progenitor (LNEP) cells [21] .”
BackgroundCastaldi, A., Horie, M., Rieger, M., Dubourd, M., Sunohara, M., Pandit, K., Zhou, B.-Y., Offringa, I., Marconett, C., & Borok, Z. (2020) · American Journal of Physiology - Lung cellular and Molecular Physiology · doi:10.1152/ajplung.00519.2019 · Cited by 13
Zhu, D., Kusuma, G. D., Schwab, R., Chan, S. T., Tan, J. L., Saad, M. I., Leeman, K. T., Kim, C. F., Wallace, E. M., & Lim, R. (2020) · Clinical Science · doi:10.1042/cs20200859 · Cited by 12
Coles, G. L., Baglia, L. A., & Ackerman, K. G. (2015) · PLoS Genetics · doi:10.1371/journal.pgen.1005525 · Cited by 12
“Recent work suggests that type 2 AECs function as adult stem/progenitor cells to replace injured AEC 1 and AEC 2 cells [4].”
BackgroundHeterogeneous Pulmonary Response After Tracheal Occlusion: Clues to Fetal Lung Growth
Dobrinskikh, E., Al‐Juboori, S. I., Shabeka, U., Reisz, J. A., Zheng, C., & Marwan, A. I. (2019) · Journal of Surgical Research · doi:10.1016/j.jss.2019.02.015 · Cited by 12
Persistence of a novel regeneration-associated transitional cell state in pulmonary fibrosisPreprint
Kobayashi, Y., Tata, A., Konkimalla, A., Katsura, H., Lee, R. F., Ou, J., Banovich, N. E., Kropski, J. A., & Tata, P. R. (2019) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/855155 · Cited by 12
Organoids in respiratory virus research: advances and perspectives
Li, X., Xiao, H., Zhou, M., Yang, C., Yang, X., Cheng, T., Yuan, L., & Xia, N. (2025) · Molecular Biomedicine · doi:10.1186/s43556-025-00343-x · Cited by 11
“Naturally, AT2 are considered as primary ASCs in adult lung [38, 176].”
Effects of LRRK2 Inhibitors in Nonhuman Primates
Miller, G. K., Kuruvilla, S., Jacob, B., LaFranco-Scheuch, L., Bakthavatchalu, V., Flor, J., Flor, K., Ziegler, J. T., Reichard, C., Manfre, P., et al. (2023) · Toxicologic Pathology · doi:10.1177/01926233231205895 · Cited by 12
“6,7 The spectrum of findings elicited in the lungs by each compound aligned with systemic potency uniquely exhibited by each molecule, given that Compound 25 and MK-1468 were associated with potentially greater peripheral engagement as determined by sustained unbound plasma concentrations above the…”
BackgroundHuman Pluripotent Stem Cell-Derived Alveolar Organoids: Cellular Heterogeneity and Maturity
Jung, J., Yang, S., Kim, W. J., Rhee, C. K., & Hong, S. (2023) · Tuberculosis & respiratory diseases · doi:10.4046/trd.2023.0131 · Cited by 11
“Gotoh et al. 26 established a 3D co-culture system with fetal human fibroblasts to promote organoid formation, and Barkauskas et al. 23 confirmed that more organoids were formed in the fibroblast-dependent condition using pri - mary platelet-derived growth factor receptor α -positive (PDGFR α + ) lung fibroblasts.”
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Circular RNAs and their roles in idiopathic pulmonary fibrosis
Surendran, A. M., Huang, C., & Liu, L. (2024) · Respiratory Research · doi:10.1186/s12931-024-02716-2 · Cited by 13
“AEC2 serves as stem cells within lung tissues [145].”
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“Subsequently, immunohistochemistry (IHC) was employed to assess the expression of pulmonary surfactant proteins (SFTPC), known marker of alveolar type II cells (AT2) 56 .”
Truncated NTRK2 is induced in CAP1 endothelial cells during mouse lung injury-repair
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Fibroblast Growth Factors in Lung Development and Regeneration: Mechanisms and Therapeutic Potential
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“The mechanisms of alveolar repair in adult lung primarily involve the proliferation of alveolar type II cell population and their differentiation into alveolar type I cells, which are crucial for gas exchange processes [14].”
Rebalancing viral and immune damage versus repair prevents death from lethal influenza infection
Ichise, H., Speranza, E. E., Russa, F. L., Veres, T. Z., Chu, C. J., Gola, A., Clark, B., & Germain, R. N. (2025) · Science · doi:10.1126/science.adr4635 · Cited by 14
Lung stem cells in regeneration and tumorigenesis
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Defense of COVID-19 by Human Organoids
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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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