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 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.