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Antifibrotic effect of lung-resident progenitor cells with high aldehyde dehydrogenase activity

BACKGROUND: Aldehyde dehydrogenase (ALDH) is highly expressed in stem/progenitor cells in various tissues, and cell populations with high ALDH activity (ALDH(br)) are associated with tissue repair. However, little is known about lung-resident ALDH(br). This study was performed to clarify the charact...

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Autores principales: Takahashi, Hiroshi, Nakashima, Taku, Masuda, Takeshi, Namba, Masashi, Sakamoto, Shinjiro, Yamaguchi, Kakuhiro, Horimasu, Yasushi, Miyamoto, Shintaro, Iwamoto, Hiroshi, Fujitaka, Kazunori, Hamada, Hironobu, Hattori, Noboru
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8381511/
https://www.ncbi.nlm.nih.gov/pubmed/34425896
http://dx.doi.org/10.1186/s13287-021-02549-6
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author Takahashi, Hiroshi
Nakashima, Taku
Masuda, Takeshi
Namba, Masashi
Sakamoto, Shinjiro
Yamaguchi, Kakuhiro
Horimasu, Yasushi
Miyamoto, Shintaro
Iwamoto, Hiroshi
Fujitaka, Kazunori
Hamada, Hironobu
Hattori, Noboru
author_facet Takahashi, Hiroshi
Nakashima, Taku
Masuda, Takeshi
Namba, Masashi
Sakamoto, Shinjiro
Yamaguchi, Kakuhiro
Horimasu, Yasushi
Miyamoto, Shintaro
Iwamoto, Hiroshi
Fujitaka, Kazunori
Hamada, Hironobu
Hattori, Noboru
author_sort Takahashi, Hiroshi
collection PubMed
description BACKGROUND: Aldehyde dehydrogenase (ALDH) is highly expressed in stem/progenitor cells in various tissues, and cell populations with high ALDH activity (ALDH(br)) are associated with tissue repair. However, little is known about lung-resident ALDH(br). This study was performed to clarify the characteristics of lung-resident ALDH(br) cells and to evaluate their possible use as a tool for cell therapy using a mouse model of bleomycin-induced pulmonary fibrosis. METHODS: The characteristics of lung-resident/nonhematopoietic (CD45(−)) ALDH(br) cells were assessed in control C57BL/6 mice. The kinetics and the potential usage of CD45(−)/ALDH(br) for cell therapy were investigated in bleomycin-induced pulmonary fibrosis. Localization of transferred CD45(−)/ALDH(br) cells was determined using mCherry-expressing mice as donors. The effects of aging on ALDH expression were also assessed using aged mice. RESULTS: Lung CD45(−)/ALDH(br) showed higher proliferative and colony-forming potential than cell populations with low ALDH activity. The CD45(−)/ALDH(br) cell population, and especially its CD45(−)/ALDH(br)/PDGFRα(+) subpopulation, was significantly reduced in the lung during bleomycin-induced pulmonary fibrosis. Furthermore, mRNA expression of ALDH isoforms was significantly reduced in the fibrotic lung. When transferred in vivo into bleomycin-pretreated mice, CD45(−)/ALDH(br) cells reached the site of injury, ameliorated pulmonary fibrosis, recovered the reduced expression of ALDH mRNA, and prolonged survival, which was associated with the upregulation of the retinol-metabolizing pathway and the suppression of profibrotic cytokines. The reduction in CD45(−)/ALDH(br)/PDGFRα(+) population was more remarkable in aged mice than in young mice. CONCLUSIONS: Our results strongly suggest that the lung expression of ALDH and lung-resident CD45(−)/ALDH(br) cells are involved in pulmonary fibrosis. The current study signified the possibility that CD45(−)/ALDH(br) cells could find application as novel and useful cell therapy tools in pulmonary fibrosis treatment. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13287-021-02549-6.
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spelling pubmed-83815112021-08-23 Antifibrotic effect of lung-resident progenitor cells with high aldehyde dehydrogenase activity Takahashi, Hiroshi Nakashima, Taku Masuda, Takeshi Namba, Masashi Sakamoto, Shinjiro Yamaguchi, Kakuhiro Horimasu, Yasushi Miyamoto, Shintaro Iwamoto, Hiroshi Fujitaka, Kazunori Hamada, Hironobu Hattori, Noboru Stem Cell Res Ther Research BACKGROUND: Aldehyde dehydrogenase (ALDH) is highly expressed in stem/progenitor cells in various tissues, and cell populations with high ALDH activity (ALDH(br)) are associated with tissue repair. However, little is known about lung-resident ALDH(br). This study was performed to clarify the characteristics of lung-resident ALDH(br) cells and to evaluate their possible use as a tool for cell therapy using a mouse model of bleomycin-induced pulmonary fibrosis. METHODS: The characteristics of lung-resident/nonhematopoietic (CD45(−)) ALDH(br) cells were assessed in control C57BL/6 mice. The kinetics and the potential usage of CD45(−)/ALDH(br) for cell therapy were investigated in bleomycin-induced pulmonary fibrosis. Localization of transferred CD45(−)/ALDH(br) cells was determined using mCherry-expressing mice as donors. The effects of aging on ALDH expression were also assessed using aged mice. RESULTS: Lung CD45(−)/ALDH(br) showed higher proliferative and colony-forming potential than cell populations with low ALDH activity. The CD45(−)/ALDH(br) cell population, and especially its CD45(−)/ALDH(br)/PDGFRα(+) subpopulation, was significantly reduced in the lung during bleomycin-induced pulmonary fibrosis. Furthermore, mRNA expression of ALDH isoforms was significantly reduced in the fibrotic lung. When transferred in vivo into bleomycin-pretreated mice, CD45(−)/ALDH(br) cells reached the site of injury, ameliorated pulmonary fibrosis, recovered the reduced expression of ALDH mRNA, and prolonged survival, which was associated with the upregulation of the retinol-metabolizing pathway and the suppression of profibrotic cytokines. The reduction in CD45(−)/ALDH(br)/PDGFRα(+) population was more remarkable in aged mice than in young mice. CONCLUSIONS: Our results strongly suggest that the lung expression of ALDH and lung-resident CD45(−)/ALDH(br) cells are involved in pulmonary fibrosis. The current study signified the possibility that CD45(−)/ALDH(br) cells could find application as novel and useful cell therapy tools in pulmonary fibrosis treatment. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13287-021-02549-6. BioMed Central 2021-08-23 /pmc/articles/PMC8381511/ /pubmed/34425896 http://dx.doi.org/10.1186/s13287-021-02549-6 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
Takahashi, Hiroshi
Nakashima, Taku
Masuda, Takeshi
Namba, Masashi
Sakamoto, Shinjiro
Yamaguchi, Kakuhiro
Horimasu, Yasushi
Miyamoto, Shintaro
Iwamoto, Hiroshi
Fujitaka, Kazunori
Hamada, Hironobu
Hattori, Noboru
Antifibrotic effect of lung-resident progenitor cells with high aldehyde dehydrogenase activity
title Antifibrotic effect of lung-resident progenitor cells with high aldehyde dehydrogenase activity
title_full Antifibrotic effect of lung-resident progenitor cells with high aldehyde dehydrogenase activity
title_fullStr Antifibrotic effect of lung-resident progenitor cells with high aldehyde dehydrogenase activity
title_full_unstemmed Antifibrotic effect of lung-resident progenitor cells with high aldehyde dehydrogenase activity
title_short Antifibrotic effect of lung-resident progenitor cells with high aldehyde dehydrogenase activity
title_sort antifibrotic effect of lung-resident progenitor cells with high aldehyde dehydrogenase activity
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8381511/
https://www.ncbi.nlm.nih.gov/pubmed/34425896
http://dx.doi.org/10.1186/s13287-021-02549-6
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