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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AEC2s can require the presence of a mesenchymal feeder layer to give rise to organoids.
“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
AEC2-derived organoids can differentiate into alveolar epithelial type 1 (AEC1) cells.
“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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“Normal maintenance of the alveolar epithelium is accomplished through the proliferation of AT2 cells, a facultative stem cell that produces and secretes pulmonary surfactant in its quiescent state (15).”
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Chanda, D., Otoupalova, E., Smith, S. R., Volckaert, T., Langhe, S. D., & Thannickal, V. J. (2018) · Molecular Aspects of Medicine · doi:10.1016/j.mam.2018.08.004 · Cited by 513 · see citing works
“In addition, these studies have revealed that specific cell progenitors within the mammalian respiratory system regenerate after injury through the activation of stem/progenitor populations or through proliferationinduced cellular expansion (Barkauskas et al., 2013; Peng et al., 2015; Warburton et al., 2008; Zacharias…”
BackgroundLung regeneration: mechanisms, applications and emerging stem cell populations
Kotton, D. N., & Morrisey, E. E. (2014) · Nature Medicine · doi:10.1038/nm.3642 · Cited by 512 · see citing works
Capillary cell-type specialization in the alveolus
Gillich, A., Zhang, F., Farmer, C. G., Travaglini, K. J., Tan, S. Y., Gu, M., Zhou, B., Feinstein, J. A., Krasnow, M. A., & Metzger, R. J. (2020) · Nature · doi:10.1038/s41586-020-2822-7 · Cited by 490 · see citing works
The aging lung: Physiology, disease, and immunity
Schneider, J. L., Rowe, J. H., Garcia-de-Alba, C., Kim, C. F., Sharpe, A. H., & Haigis, M. C. (2021) · Cell · doi:10.1016/j.cell.2021.03.005 · Cited by 500 · see citing works
“They regenerate after injury by proliferating and differentiating into AT1 cells that are critical to maintain gas exchange (Barkauskas et al., 2013).”
TGF-β Signaling in Lung Health and Disease
Saito, A., Horie, M., & Nagase, T. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19082460 · Cited by 501 · see citing works
“It is thought that alveolar epithelial type II cells contribute to alveolar homeostasis by self-renewing and differentiating into type I cells [55].”
BackgroundLee, J., Bhang, D. H., Beede, A. M., Huang, T. L., Stripp, B. R., Bloch, K. D., Wagers, A. J., Tseng, Y., Ryeom, S. W., & Kim, C. F. (2014) · Cell · doi:10.1016/j.cell.2013.12.039 · Cited by 491 · see citing works
“%) of total platelet α granule content during platelet activation (Baenziger et al., 1971; Ganguly, 1971; Lawler et al., 1978).”
BackgroundSelf-citationHuman organoids in basic research and clinical applications
Tang, X.-Y., Wu, S., Wang, D., Chu, C., Hong, Y., Tao, M., Hu, H., Xu, M., Guo, X. L., & Liu, Y. (2022) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-022-01024-9 · Cited by 509 · see citing works
“Based on the regenerative capacity of lung cells, many groups have generated organoids from mouse and human airway basal cells,(123,127,128) airway secretory club cells(124,129,130) and AECIIs.(125,131) Due to the possibility of reproducing lung tissue in vitro and their ability to simulate important gas exchange func…”
BackgroundLung organoids: current uses and future promise
Barkauskas, C. E., Chung, M.-I., Fioret, B. A., Gao, X., Katsura, H., & Hogan, B. L. M. (2017) · Development · doi:10.1242/dev.140103 · Cited by 447 · see citing works
“…DMEM/F12 supplemented with ITS, EGF, BPE, CTX, 5% FBS, antibiotics; RA freshly added; Y-27632 (ROCK inhibitor) for the first 2 days Barkauskas et al., 2013 Surface markers Lung mesenchymal cells (EpCAM− Sca1+) DMEM/F12 supplemented with ITS, 10% newborn calf serum, glutamine,…”
BackgroundMethodInfluentialSelf-citationProgenitor identification and SARS-CoV-2 infection in human distal lung organoids
Salahudeen, A. A., Choi, S. S., Rustagi, A., Zhu, J., van Unen, V., de la O, S. M., Flynn, R. A., Margalef-Català, M., Santos, A. J. M., Ju, J., et al. (2020) · Nature · doi:10.1038/s41586-020-3014-1 · Cited by 416 · see citing works
Katsura, H., Sontake, V., Tata, A., Kobayashi, Y., Edwards, C. E., Heaton, B. E., Konkimalla, A., Asakura, T., Mikami, Y., Fritch, E. J., et al. (2020) · Cell Stem Cell · doi:10.1016/j.stem.2020.10.005 · Cited by 416 · see citing works
“Alveolosphere culture Mouse conventional Alveolosphere culture (using MTEC medium) was performed as described previously (Barkauskas et al., 2013).”
Self-citationProgressive Pulmonary Fibrosis Is Caused by Elevated Mechanical Tension on Alveolar Stem Cells
Wu, H., Yu, Y., Huang, H., Hu, Y., Fu, S., Wang, Z., Shi, M., Zhao, X., Yuan, J., Li, J., et al. (2019) · Cell · doi:10.1016/j.cell.2019.11.027 · Cited by 422 · see citing works
The Cellular and Physiological Basis for Lung Repair and Regeneration: Past, Present, and Future
Basil, M. C., Katzen, J., Engler, A. E., Guo, M., Herriges, M. J., Kathiriya, J. J., Windmueller, R., Ysasi, A. B., Zacharias, W. J., Chapman, H. A., et al. (2020) · Cell Stem Cell · doi:10.1016/j.stem.2020.03.009 · Cited by 414 · see citing works
“A number of distinct, small populations of progenitor cell types have been reported to contribute to regeneration of distal airway epithelia after injury in mice, which lacks basal cells (Barkauskas et al., 2013; Bertoncello and McQualter, 2010; Chen, 2017; Perl et al., 2005) .”
BackgroundInfluentialInfluenza virus and SARS-CoV-2: pathogenesis and host responses in the respiratory tract
Flerlage, T., Boyd, D. F., Meliopoulos, V., Thomas, P. G., & Schultz‐Cherry, S. (2021) · Nature Reviews Microbiology · doi:10.1038/s41579-021-00542-7 · Cited by 406 · see citing works
Lung Cancers: Molecular Characterization, Clonal Heterogeneity and Evolution, and Cancer Stem Cells
Testa, U., Castelli, G., & Pelosi, E. (2018) · Cancers · doi:10.3390/cancers10080248 · Cited by 406 · see citing works
Assembly of embryonic and extraembryonic stem cells to mimic embryogenesis in vitro
Harrison, S., Sözen, B., Christodoulou, N., Kyprianou, C., & Zernicka‐Goetz, M. (2017) · Science · doi:10.1126/science.aal1810 · Cited by 393 · see citing works
“ESCs retain pluripotency and have the ability to be directed to develop into organoids that present an invaluable system to recapitulate many aspects of organ formation in vitro (17-22).”
Alveolar Epithelial Type II Cells as Drivers of Lung Fibrosis in Idiopathic Pulmonary Fibrosis
Parimon, T., Yao, C., Stripp, B. R., Noble, P. W., & Chen, P. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21072269 · Cited by 386 · see citing works
“Lineage tracing experiments in mice show that AT2 cells defined by their expression of surfactant protein C (Sftpc/SFTPC) are capable of long-term self-renewal and multipotent differentiation to yield alveolar type I (AT1) cells; two characteristics that suggest either the AT2 population as a whole or a subset of AT2…”
BackgroundSelf-citationDisease modelling in human organoids
Lancaster, M. A., & Huch, M. (2019) · Disease Models & Mechanisms · doi:10.1242/dmm.039347 · Cited by 379 · see citing works
“Similarly, Barkauskas et al., by co-culturing human AT2 cells with lung fibroblasts, established self-renewing human alveolar organoids (Barkauskas et al., 2013).”
Anatomically and Functionally Distinct Lung Mesenchymal Populations Marked by Lgr5 and Lgr6
Lee, J., Tammela, T., Hofree, M., Choi, J., Marjanovic, N. D., Han, S., Canner, D. A., Wu, K., Paschini, M., Bhang, D. H., et al. (2017) · Cell · doi:10.1016/j.cell.2017.07.028 · Cited by 362 · see citing works
“The Lgr5 mesenchymal cells, which we found support alveolar differentiation, appear to be distinct from Pdgfra cells (Figures 2C–2E), which have been known to promote AT2 self-renewal and differentiation (Barkauskas et al., 2013).”
BackgroundTissue homeostasis and inflammation
Meizlish, M. L., Franklin, R. A., Zhou, X., & Medzhitov, R. (2021) · Annual Review of Immunology · doi:10.1146/annurev-immunol-061020-053734 · Cited by 364 · see citing works
El Agha, E., Moiseenko, A., Kheirollahi, V., De Langhe, S., Crnkovic, S., Kwapiszewska, G., Szibor, M., Kosanovic, D., Schwind, F., Schermuly, R. T., et al. (2017) · Cell Stem Cell · doi:10.1016/j.stem.2016.10.004 · Cited by 347 · see citing works
“Lipofibroblasts are implicated in alveolar maturation and surfactant production (Rehan and Torday, 2014) and have been proposed to contribute to the epithelial stem-cell niche in adult mouse lungs (Barkauskas et al., 2013; McQualter et al., 2013).”
Meiners, S., Eickelberg, O., & Königshoff, M. (2015) · European Respiratory Journal · doi:10.1183/09031936.00186914 · Cited by 340 · see citing works
Telomere dysfunction causes alveolar stem cell failure
Alder, J. K., Barkauskas, C. E., Limjunyawong, N., Stanley, S. E., Kembou, F., Tuder, R. M., Hogan, B. L. M., Mitzner, W., & Armanios, M. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1504780112 · Cited by 339 · see citing works
“These structures are comprised exclusively of AEC2s that have both self-renewed and differentiated into type 1 alveolar epithelial cells (AEC1s) (14).”
BackgroundSelf-citationHuang, J., Hume, A. J., Abo, K. M., Werder, R. B., Villacorta-Martín, C., Alysandratos, K., Beermann, M. L., Simone-Roach, C., Lindstrom-Vautrin, J., Olejnik, J., et al. (2020) · Cell stem cell · doi:10.1016/j.stem.2020.09.013 · Cited by 330 · see citing works
“A limitation of our study is the observation that iAT2s in our culture conditions do not generate alveolar type 1 (AT1)-like cells, an ability that is similarly lacking in other published reports of in vitro cultures of both iPSC-derived and primary human AT2s to date (Barkauskas et al., 2013).”
Accelerated ageing of the lung in COPD: new concepts
Mercado, N., Ito, K., & Barnes, P. J. (2015) · Thorax · doi:10.1136/thoraxjnl-2014-206084 · Cited by 340 · see citing works
Gotoh, S., Ito, I., Nagasaki, T., Yamamoto, Y., Konishi, S., Korogi, Y., Matsumoto, H., Muro, S., Hirai, T., Funato, M., et al. (2014) · Stem Cell Reports · doi:10.1016/j.stemcr.2014.07.005 · Cited by 328 · see citing works
“The protocol for the 3D culture was modified from a previous report (Barkauskas et al., 2013).”
BackgroundHuman distal airways contain a multipotent secretory cell that can regenerate alveoli
Basil, M. C., Cardenas‐Diaz, F. L., Kathiriya, J. J., Morley, M. P., Carl, J., Brumwell, A. N., Katzen, J. B., Slovik, K. J., Babu, A., Zhou, S., et al. (2022) · Nature · doi:10.1038/s41586-022-04552-0 · Cited by 328 · see citing works
Chung, M.-I., Bujnis, M. N., Barkauskas, C. E., Kobayashi, Y., & Hogan, B. L. M. (2018) · Development · doi:10.1242/dev.163014 · Cited by 311 · see citing works
“A number of studies have explored roles for these different components in models of lung repair and regeneration (Barkauskas et al., 2013; Chen et al., 2012; Ding et al., 2011; Jain et al., 2015a; Lechner et al., 2017; Lee et al., 2014; Liu et al., 2015, 2016; Nabhan et al., 2018; Rafii et al.,…”
BackgroundMethodInfluentialSelf-citationIdiopathic pulmonary fibrosis: Epithelial-mesenchymal interactions and emerging therapeutic targets
Hewlett, J. C., Kropski, J. A., & Blackwell, T. S. (2018) · Matrix Biology · doi:10.1016/j.matbio.2018.03.021 · Cited by 327 · see citing works
“contribute to epithelial repair in different conditions and experimental models (Reviewed in [60, 61]), including basal cells [62], club/Clara cells [63, 64], bronchoalveolar stem cells (BASCs), lineage-negative epithelial progenitor cells (LNEPs) [65] type II alveolar epithelial cells (AEC2s) [66], and subsets of AEC…”
BackgroundLung regeneration by multipotent stem cells residing at the bronchioalveolar-duct junction
Liu, Q., Liu, K., Cui, G., Huang, X., Yao, S., Guo, W., Qin, Z., Li, Y., Yang, R., Pu, W., et al. (2019) · Nature Genetics · doi:10.1038/s41588-019-0346-6 · Cited by 320 · see citing works
Alveolar fibroblast lineage orchestrates lung inflammation and fibrosis
Tsukui, T., Wolters, P. J., & Sheppard, D. (2024) · Nature · doi:10.1038/s41586-024-07660-1 · Cited by 318 · see citing works
“Previous work showed that PDGFRA + lipofibroblasts in alveolar walls are closely associated with alveolar type 2 epithelial (AT2) cells and can support the growth of AT2 cells ex vivo 11,12 .”
FLASH Irradiation Spares Lung Progenitor Cells and Limits the Incidence of Radio-induced Senescence
Fouillade, C., Curras-Alonso, S., Giuranno, L., Quelennec, E., Heinrich, S., Bonnet-Boissinot, S., Beddok, A., Leboucher, S., Karakurt, H. U., Bohec, M., et al. (2019) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-19-1440 · Cited by 311 · see citing works
“In line with this result, our scRNAseq analysis reveals that after CONV irradiation, the expression of Egr1, a transcription factor whose downregulation is necessary to trigger proliferation of hematopoietic stem cells (19), is reduced specifically in the AT2 compartment which is known to contain a stem/progenitor poo…”
ResultPlasticity of Hopx(+) type I alveolar cells to regenerate type II cells in the lung
Jain, R., Barkauskas, C. E., Takeda, N., Bowie, E. J., Aghajanian, H., Wang, Q., Padmanabhan, A., Manderfield, L. J., Gupta, M., Li, D., et al. (2015) · Nature Communications · doi:10.1038/ncomms7727 · Cited by 303 · see citing works
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Self-citationChambers, D. C., Enever, D., Ilic, N., Sparks, L., Whitelaw, K., Ayres, J., Yerkovich, S. T., Khalil, D., Atkinson, K. M., & Hopkins, P. M. A. (2014) · Respirology · doi:10.1111/resp.12343 · Cited by 278 · see citing works
Yap/Taz regulate alveolar regeneration and resolution of lung inflammation
LaCanna, R., Liccardo, D., Zhang, P., Tragesser, L. E., Wang, Y., Cao, T., Chapman, H. A., Morrisey, E. E., Shen, H., Koch, W. J., et al. (2019) · Journal of Clinical Investigation · doi:10.1172/jci125014 · Cited by 290 · see citing works
“Lineage tracing of SPC+ AECIIs demonstrates their capacities of selfrenewal and differentiation into AECIs during both the homeostatic state and regeneration after injury (4).”
Contributions of alveolar epithelial cell quality control to pulmonary fibrosis
Katzen, J. B., & Beers, M. F. (2020) · Journal of Clinical Investigation · doi:10.1172/jci139519 · Cited by 289 · see citing works
“A central role for the AT2 cell in IPF is, in part, due to its critical function in alveolar niche homeostasis through the production of pulmonary surfactant (12) and as a progenitor cell to both self-renew and transdifferentiate into AT1 cells (13).”
BackgroundCao, Z., Lis, R., Ginsberg, M., Chavez, D., Shido, K., Rabbany, S., Fong, G., Sakmar, T., Rafii, S., & Ding, B. (2016) · Nature Medicine · doi:10.1038/nm.4035 · Cited by 253 · see citing works
Pathogenesis of chronic obstructive pulmonary disease (COPD) induced by cigarette smoke
Hikichi, M., Mizumura, K., Maruoka, S., & Gon, Y. (2019) · Journal of Thoracic Disease · doi:10.21037/jtd.2019.10.43 · Cited by 294 · see citing works
“Senescence of the mesenchymal stem cells (fibroblasts and endothelial cells) and alveolar type II cells that are differentiated into alveolar type I cells are reported to develop emphysematous lesions and COPD (69,70).”
BackgroundThree-dimensional human alveolar stem cell culture models reveal infection response to SARS-CoV-2
Youk, J., Kim, T., Evans, K. V., Jeong, Y.-I., Hur, Y., Hong, S. P., Kim, J. H., Yi, K., Kim, S. Y., Na, K. J., et al. (2020) · Cell Stem Cell · doi:10.1016/j.stem.2020.10.004 · Cited by 266 · see citing works
“Further, HTII-280+ hAT2 cells expressing HOPX were also observed in our h3ACs, as well as in alveolar tissue sections (Travaglini et al., 2020) (Figures S1C and S1D).”
InfluentialBody Localization of ACE-2: On the Trail of the Keyhole of SARS-CoV-2
Salamanna, F., Maglio, M., Landini, M. P., & Fini, M. (2020) · Frontiers in Medicine · doi:10.3389/fmed.2020.594495 · Cited by 283 · see citing works
“These type of pneumocytes exert immunoregulatory functions and are of key importance for alveolar surfactant production and they also function as stem cells, progenitors of type I pneumocytes, that represent the 95% of all pneumocytes and that are responsible of gas exchanges (142).”
BackgroundSox9 plays multiple roles in the lung epithelium during branching morphogenesis
Rockich, B. E., Hrycaj, S., Shih, H.-P., Nagy, M. S., Ferguson, M. A. H., Kopp, J. L., Sander, M., Wellik, D. M., & Spence, J. R. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1311847110 · Cited by 267 · see citing works
“However, Sftpc in the early lung marks all distal tip progenitor cells, and recent studies have demonstrated that Sftpc-positive cells in the adult are alveolar stem cells (41).”
BackgroundNikolić, M., Caritg, O., Jeng, Q., Johnson, J.-A., Sun, D., Howell, K. J., Brady, J., Laresgoiti, U., Allen, G. E., Butler, R., et al. (2017) · eLife · doi:10.7554/elife.26575 · Cited by 270 · see citing works
“In the adult human lung, pro-SFTPC (Surfactant Protein C, or SPC) and a monoclonal antibody, HTII280, are markers of AT2 cells (Figure 1C) (Barkauskas et al., 2013; Gonzalez et al., 2010).”
BackgroundFrank, D. B., Peng, T., Zepp, J. A., Snitow, M. E., Vincent, T. L., Penkala, I. J., Cui, Z., Herriges, M. J., Morley, M. P., Zhou, S., et al. (2016) · Cell Reports · doi:10.1016/j.celrep.2016.11.001 · Cited by 277 · see citing works
Cellular crosstalk in the development and regeneration of the respiratory system
Zepp, J. A., & Morrisey, E. E. (2019) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-019-0141-3 · Cited by 265 · see citing works
Long-term expansion of alveolar stem cells derived from human iPS cells in organoids
Yamamoto, Y., Gotoh, S., Korogi, Y., Seki, M., Konishi, S., Ikeo, S., Sone, N., Nagasaki, T., Matsumoto, H., Muro, S., et al. (2017) · Nature Methods · doi:10.1038/nmeth.4448 · Cited by 268 · see citing works
Local lung hypoxia determines epithelial fate decisions during alveolar regeneration
Xi, Y., Kim, T., Brumwell, A. N., Driver, I. H., Wei, Y., Tan, V. M., Jackson, J., Xu, J., Lee, D.-K., Gotts, J. E., et al. (2017) · Nature Cell Biology · doi:10.1038/ncb3580 · Cited by 268 · see citing works
Deciphering the cells of origin of squamous cell carcinomas
Sánchez‐Danés, A., & Blanpain, C. (2018) · Nature reviews. Cancer · doi:10.1038/s41568-018-0024-5 · Cited by 265 · see citing works
Epithelial–Mesenchymal Transition in the Pathogenesis of Idiopathic Pulmonary Fibrosis
Salton, F., Volpe, M., & Confalonieri, M. (2019) · Medicina · doi:10.3390/medicina55040083 · Cited by 264 · see citing works
Human alveolar type 2 epithelium transdifferentiates into metaplastic KRT5+ basal cells
Kathiriya, J. J., Wang, C., Zhou, M., Brumwell, A. N., Cassandras, M., Saux, C. J. L., Cohen, M., Alysandratos, K., Wang, B., Wolters, P. J., et al. (2021) · Nature Cell Biology · doi:10.1038/s41556-021-00809-4 · Cited by 267 · see citing works
“(a) Immunostaining of IPF lung with AEC2, ABIs, and basal markers show (1) linearly connected AEC2, ABI1, ABI2, and basal cell, (2) a cluster of basal cells (KRT17+/ KRT5+/TP63+), and two types of ABI2s (KRT17+/KRT5−): (3) TP63neg and (4) TP63pos.”
SARS-CoV-2 infection of primary human lung epithelium for COVID-19 modeling and drug discovery
Mulay, A., Konda, B. M., Garcia, G., Yao, C., Beil, S., Villalba, J. M., Koziol, C., Sen, C., Purkayastha, A., Kolls, J. K., et al. (2021) · Cell Reports · doi:10.1016/j.celrep.2021.109055 · Cited by 256 · see citing works
“Scale bar: 20 mm. (C) Comparison of percentage of cells staining positive for CC3 in intact Matrigel-embedded MOCK alveospheres, alveolar cultures dispersed from Matrigel, and infected cultures dispersed from Matrigel. n = 7 (one-way ANOVA with Tukey’s post hoc test).”
InfluentialSelf-citationRecruited Monocytes and Type 2 Immunity Promote Lung Regeneration following Pneumonectomy
Lechner, A. J., Driver, I. H., Lee, J., Conroy, C., Nagle, A., Locksley, R. M., & Rock, J. R. (2017) · Cell stem cell · doi:10.1016/j.stem.2017.03.024 · Cited by 255 · see citing works
“Macrophages Support AEC2 in Culture To better understand how macrophages might regulate AEC2 behavior, we modified an organoid assay in which AEC2s are sorted and cultured in Matrigel and supplemented growth medium (Barkauskas et al., 2013).”
InfluentialModeling of fibrotic lung disease using 3D organoids derived from human pluripotent stem cells
Strikoudis, A., Cieślak, A., Loffredo, L., Chen, Y.-W., Patel, N., Saqi, A., Lederer, D. J., & Snoeck, H.-W. (2019) · Cell Reports · doi:10.1016/j.celrep.2019.05.077 · Cited by 242 · see citing works
Expression of mutant Sftpc in murine alveolar epithelia drives spontaneous lung fibrosis
Nureki, S., Tomer, Y., Venosa, A., Katzen, J. B., Russo, S. J., Jamil, S., Barrett, M., Nguyen, V., Kopp, M. C., Mulugeta, S., et al. (2018) · Journal of Clinical Investigation · doi:10.1172/jci99287 · Cited by 249 · see citing works
Kathiriya, J. J., Brumwell, A. N., Jackson, J. R., Tang, X., & Chapman, H. A. (2020) · Cell Stem Cell · doi:10.1016/j.stem.2019.12.014 · Cited by 246 · see citing works
“In the injured lung parenchyma, both remaining type II cells (AEC2s) and stem/progenitors emanating from distal airways contribute importantly to alveolar repair (Barkauskas et al., 2013; Kumar et al., 2011; McQualter, 2019; Zacharias et al., 2018; Zheng et al., 2017).”
BackgroundMethodInfluentialJin Bing, P. A. N., Li, D., Xu, Y., Zhang, J., Wang, Y., Chen, M., Lin, S., Huang, L., Chung, E. J., Citrin, D. E., et al. (2017) · International Journal of Radiation Oncology*Biology*Physics · doi:10.1016/j.ijrobp.2017.02.216 · Cited by 244 · see citing works
Pulmonary alveolar type I cell population consists of two distinct subtypes that differ in cell fate
Wang, Y., Tang, Z., Huang, H., Li, J., Wang, Z., Yu, Y., Zhang, C., Li, J., Dai, H., Wang, F., et al. (2018) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1719474115 · Cited by 233 · see citing works
“We also monitored Igfbp2 expression in experiments with 3D alveolar-like organoids (1).”
MethodMAPK-Mediated YAP Activation Controls Mechanical-Tension-Induced Pulmonary Alveolar Regeneration
Liu, Z., Wu, H., Jiang, K., Wang, Y., Zhang, W., Chu, Q., Li, J., Huang, H., Cai, T., Ji, H., et al. (2016) · Cell Reports · doi:10.1016/j.celrep.2016.07.020 · Cited by 239 · see citing works
“1810 Cell Reports 16, 1810–1819, August 16, 2016 a 2016 The Autho This is an open access article under the CC BY-NC-ND license (http:// function as alveolar stem cells in adult lungs (Barkauskas et al., 2013; Desai et al., 2014; Rock et al., 2011).”
Evans, C. M., Fingerlin, T. E., Schwarz, M. I., Lynch, D. A., Kurche, J. S., Warg, L. A., Yang, I. V., & Schwartz, D. A. (2016) · Physiological Reviews · doi:10.1152/physrev.00004.2016 · Cited by 233 · see citing works
“In IPF, however, type 2 alveolar epithelial cell hyperplasia persists replacing type 1 cells and likely contributes to collagen accumulation both by the release of fibroblast growth factors, and by transitioning to fibroblasts and eventually myofibroblasts (epithelial-mesenchymal transition) (6, 180, 229).”
BackgroundLamers, M. M., van der Vaart, J., Knoops, K., Riesebosch, S., Breugem, T. I., Mykytyn, A. Z., Beumer, J., Schipper, D., Bezstarosti, K., Koopman, C. D., et al. (2021) · The EMBO Journal · doi:10.15252/embj.2020105912 · Cited by 227 · see citing works
“In human fetal development, alveolar cells are derived from bipotent progenitor cells, whereas in adults, ATI cells are derived from a rare self-renewing population of ATII cells (Barkauskas et al , 2013; Nikolic et al , 2017).”
Defining Adult Stem Cells by Function, not by Phenotype
Clevers, H. C., & Watt, F. M. (2018) · Annual Review of Biochemistry · doi:10.1146/annurev-biochem-062917-012341 · Cited by 226 · see citing works
Epithelial Vegfa Specifies a Distinct Endothelial Population in the Mouse Lung
Ellis, L. V., Cain, M. P., Hutchison, V., Flodby, P., Crandall, E. D., Borok, Z., Zhou, B., Ostrin, E. J., Wythe, J. D., & Chen, J. (2020) · Developmental Cell · doi:10.1016/j.devcel.2020.01.009 · Cited by 234 · see citing works
The Strength of Mechanical Forces Determines the Differentiation of Alveolar Epithelial Cells
Li, J., Wang, Z., Chu, Q., Jiang, K., Li, J., & Tang, N. (2018) · Developmental Cell · doi:10.1016/j.devcel.2018.01.008 · Cited by 226 · see citing works
Human lung development: recent progress and new challenges
Nikolić, M., Sun, D., & Rawlins, E. L. (2018) · Development · doi:10.1242/dev.163485 · Cited by 230 · see citing works
“AT2 cells are the major alveolar epithelial stem cell as they can both self-renew and differentiate into AT1 cells (Barkauskas et al., 2013; Desai et al., 2014; Rock et al., 2011a).”
BackgroundRare Pulmonary Neuroendocrine Cells Are Stem Cells Regulated by Rb, p53, and Notch
Ouadah, Y., Rojas, E., Riordan, D. P., Capostagno, S., Kuo, C. S., & Krasnow, M. A. (2019) · Cell · doi:10.1016/j.cell.2019.09.010 · Cited by 219 · see citing works
Healing after COVID-19: are survivors at risk for pulmonary fibrosis?
McDonald, L. T. (2020) · American Journal of Physiology-Lung Cellular and Molecular Physiology · doi:10.1152/ajplung.00238.2020 · Cited by 223 · see citing works
Lung ageing and COPD: is there a role for ageing in abnormal tissue repair?
Brandsma, C.-A., de Vries, M., Costa, R., Woldhuis, R. R., Königshoff, M., & Timens, W. (2017) · European Respiratory Review · doi:10.1183/16000617.0073-2017 · Cited by 221 · see citing works
Novel aspects of pathogenesis and regeneration mechanisms in COPD
Aldonytė, R., Bagdonas, E., Raudoniūtė, J., & Bružauskaitė, I. (2015) · International Journal of COPD · doi:10.2147/copd.s82518 · Cited by 213 · see citing works
“206 They show that type II epithelial cells can self-renew in culture and differentiate into alveolar-like structures “alveolospheres” containing type II and type I epithelial cells.”
Derivation of self-renewing lung alveolar epithelial type II cells from human pluripotent stem cells
Jacob, A., Vedaie, M., Roberts, D. A., Thomas, D. C., Villacorta-Martín, C., Alysandratos, K., Hawkins, F. J., & Kotton, D. N. (2019) · Nature Protocols · doi:10.1038/s41596-019-0220-0 · Cited by 211 · see citing works
Lange, A. W., Sridharan, A., Xu, Y. J., Stripp, B. R., Perl, A. T., & Whitsett, J. A. (2014) · Journal of Molecular Cell Biology · doi:10.1093/jmcb/mju046 · Cited by 208 · see citing works
“D ow nloaded from https://academ ic.oup.com /jm cb/article-abstract/7/1/35/877891 by guest on 15 M arch 2020 mature lung (Yin et al., 2006; Barkauskas et al., 2013).”
BackgroundSelf-citationBuilding and Regenerating the Lung Cell by Cell
Whitsett, J. A., Kalin, T. V., Xu, Y. J., & Kalinichenko, V. V. (2018) · Physiological Reviews · doi:10.1152/physrev.00001.2018 · Cited by 202 · see citing works
“Proliferative capacity is maintained in AT2 cells after birth, while AT1 cells are essentially nonproliferative even after injury (15).”
Background
- 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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