How Much Do We Know About the Mouse Respiratory Epithelial Stem Cells? Characterization of a Doxycycline-Regulated Multi-Lineage Mouse Respiratory Epithelial Precursor Cell Line In Vitro And In Vivo
Main Article Content
Abstract
Background-Purpose of this study: Tissue-specific stem cell lines are useful tools for cell biology studies. Information on respiratory tissue cell lines is limited. A doxycycline-regulated epithelial precursor cell line was established from the lung tissue of a tTAxSV40 Tag double transgenic mouse. In this study, we have characterized this cell line in vitro & in vivo, and found to mimic a rare subpopulation of club- and pneumocyte type II-dual cells.
Methods: It was partially characterized using cell viability and death assays, H3-thymidine incorporation assay, chloride efflux assay, Western blotting of proteins secreted, RT-PCR assays for RNA isolated. In addition, immune-deficient SCID mice were used as hosts for implantation of this precursor cell line, and feed with/without doxycycline containing water. Immunofluorescent typing using different antibodies were used to characterize the implanted lung.
Results: This cell line was found to mimic a rare subpopulation of club- and pneumocyte type II- dual cells with multiple phenotypes. Cell growth was doxycycline-regulated and observed only when doxycycline was omitted from the medium or present at concentrations up to 1 µg/ml, higher concentrations were inhibitory. ACT+ ciliated cells were found upon implantation into immune-deficient mice, in addition. Cell growth was doxycycline-regulated in vitro. When transplanted subcutaneously into immune-deficient mice, these cells migrated to the lung to form organized chimeric structures of donor and host origins, with club cells in the terminal bronchioles, ACT+ ciliated cells along the epithelial lining, and pneumocyte type II-cells in the alveolar interstices. No such homing of donor cells to the lung was observed when the implanted mice were fed doxycycline-containing water.
Discussions-Conclusions: This lung stem cell line might be able to provide us with an insight into the differentiation pathway of lung epithelial cells as well as with some understanding of the nature of air trophic-pulmonary epithelial cells. The results of this study underline the possibility of a future application for somatic (stem / precursor) cells in tissue replacement and tissue engineering of the damaged lung. Its ability to secrete and deliver soluble protein, might be a potential novel way for drug delivery. In addition, stem cells are thought to proliferate and differentiate in response to a deficiency or as a result of injury. Successful migration to the target organ and subsequent maturation of these precursors could be attributed to a requirement of lung stem cells to search for an aerated environment. Our findings challenge some current concepts of stem cell biology.This lung stem cell line may become a rich source of cells for tissue engineering and cell-based therapy for lung injury. The route and protocol established for cell introduction into the lung may provide a novel alternative to delivery of soluble protein substances through the airways. This lung stem cell line might also be modified to provide models for screening drugs against respiratory infection.
Keywords:
Tet-off expression system, Lung stem cells, Lung disease, Lung viral infection, Drug screening and delivery
Article Details
How to Cite
ELMSHAEUSER, Christian et al.
How Much Do We Know About the Mouse Respiratory Epithelial Stem Cells?.
Medical Research Archives, [S.l.], v. 11, n. 10, oct. 2023.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/4522>. Date accessed: 26 dec. 2024.
doi: https://doi.org/10.18103/mra.v11i10.4522.
Section
Research Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
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3. Kim CF, Jackson EL, Woolfenden AE, et al. Identification of Bronchioalveolar Stem Cells in Normal Lung and Lung Cancer. Cell 2005;121:823-835.
doi: 10.1016/j.cell.2005.03.032
4. Louie SM, Moye AL, Wong IG, et al. Progenitor potential of lung epithelial organoid cells in a transplantation model. Cell Reports 2022;39:110662-110692. doi: 10.1016/j.celrep.2022.110662
5. Muth H, Elmshauser C, Broad S, et al. Cell-based delivery of cytokines allows for the differentiation of a doxycycline inducible oligodendrocyte precursor cell line. J Gene Med 2001;3:585-597. doi: 10.1002/jgm.221.
6. Elmshaeuser C, Bechtel J, Motta I, et al. Characterization of a mouse tet-on glia precursor cell line in vitro and in vivo using the electrophysiological measurement. J Physiol Paris 2002;96:329-338. doi: 10.1016/S0928-4257(02)00024-4.
7. Chen U. Some properties and applications of cell lines and clones established from tet-responsive-SV40 Tag mice and mES cell lines. Scand. J Immunology 2011;73:531-535. doi: 10.1111/j.1365-3083.2011.02551.x
8. Milo-Landesman D, Efrat S. Growth factor-dependent proliferation of the pancreatic β-cell line βTC-tet: An assay for β-cell mitogenic factors. Int J Exp Diabetes Res 2002;3:69–74. doi: 10.1080/15604280212526
9. Efrat S, Fusco-DeMane D, Lemberg H, et al. Temporal control of gene expression in transgenic mice by a tetracycline-responsive promoter. Proc Natl Acad Sci USA 1995;92:3576-3580.
doi: 10.1073/pnas.92.8.3576
10. Hook GE, Brody AR, Cameron GS, et al. Repopulation of denuded tracheas by Clara cells isolated from the lung of rabbits. Exp Lung Res 1987;12:311-329.
doi: 10.3109/01902148709062843
11. Engelhardt JF, Zepeda M, Cohn JA, et al. Expression of the cystic fibrosis gene in adult human lung. J Clin Invest 1994;93:737-749. doi: 10.1172/JCI117028
12. Engelhardt JF. Stem cell niches in the mouse airway. Am J Respir Cell Mol Biol 2001;24:649-652.
doi: 10.1165/ajrcmb.24.6.f206
13. Tirouvanziam R, Desternes A, Puchelle E, et al. Bioelectric properties of human cystic fibrosis and non-cystic fibrosis fetal respiratory xenografts in SCID mice. Am J Physiol 1998;274: C875-882. doi: 10.1152/ajpcell.1998.274.4.C875
14. Singh G, Katyal SL. Clara cell proteins. Ann New York Acad Sci 2000;923:43-58. doi: 10.1111/j.1749-6632.2000.tb05518.x
15. Singh G, Katyal SL. An immunologic study of the secretory products of rat Clara cells. J Histochem Cytochem 1984;32:49-54. doi: 10.1177/32.1.6418790
16. Bedetti CD, Singh J, Singh G, et al. Ultrastructural localization of rat Clara cell 10 kd secretory protein by the immunologic technique using polyclonal and monoclonal antibodies. J Histochem Cytochem 1987;35:789-794.
doi: 10.1177/35.7.2438324
17. Reynolds SD, Malkinson AM. Clara cell: progenitor for the bronchiolar epithelium. Int J Biochem Cell Biol 2010;42:1-4. doi: 10.1016/j.biocel.2009.09.002
18. Stripp BR, Maxon K, Mera R. Plasticity of airway cell proliferation and gene expression after acute naphthalene injury. Am J Physiol 1995;269: L791-L799. doi: 10.1152/ajplung.1995.269.6.L791
19. Hong KU, Reynolds SD, Watkins S, et al. Basel cells are a multipotent progenitor capable of renewing the bronchial epithelium. J Pathol 2004;164:577-588. doi: 10.1016/S0002-9440(10)63147-1
20. Borthwick DW, Shahbazian M, Krantz TQ, et al. Evidence for stem-cell niches in the tracheal epithelium. Am J Respir Cell Mol Biol 2001;24;662-670.
doi: 10.1165/ajrcmb.24.6.4217
21. Fehrenbach H. Alveolar epithelial type II cell: defender of the alveolus revisited. Respir Res 2001;2:33-46. doi: 10.1186/rr36
22. Otto WR. Lung epithelial stem cells. J Pathology 2002;197:527-535. doi: 10.1002/path.1160
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