Abstract
BackgroundAldehyde dehydrogenase (ALDH) is highly expressed in stem/progenitor cells in various tissues, and cell populations with high ALDH activity (ALDHbr) are associated with tissue repair. However, little is known about lung-resident ALDHbr. This study was performed to clarify the characteristics of lung-resident ALDHbr cells and to evaluate their possible use as a tool for cell therapy using a mouse model of bleomycin-induced pulmonary fibrosis.MethodsThe characteristics of lung-resident/nonhematopoietic (CD45−) ALDHbr cells were assessed in control C57BL/6 mice. The kinetics and the potential usage of CD45−/ALDHbr for cell therapy were investigated in bleomycin-induced pulmonary fibrosis. Localization of transferred CD45−/ALDHbr cells was determined using mCherry-expressing mice as donors. The effects of aging on ALDH expression were also assessed using aged mice.ResultsLung CD45−/ALDHbr showed higher proliferative and colony-forming potential than cell populations with low ALDH activity. The CD45−/ALDHbr cell population, and especially its CD45−/ALDHbr/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−/ALDHbr 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−/ALDHbr/PDGFRα+ population was more remarkable in aged mice than in young mice.ConclusionsOur results strongly suggest that the lung expression of ALDH and lung-resident CD45−/ALDHbr cells are involved in pulmonary fibrosis. The current study signified the possibility that CD45−/ALDHbr cells could find application as novel and useful cell therapy tools in pulmonary fibrosis treatment.
Highlights
Aldehyde dehydrogenase (ALDH) is highly expressed in stem/progenitor cells in various tissues, and cell populations with high ALDH activity (ALDHbr) are associated with tissue repair
To assess lung resident Cell populations with high ALDH activity (ALDHbr), we focused on the nonhematopoietic CD45−/ALDHbr fraction
Analysis of these nonhematopoietic cells, that is, the lung resident CD45−/ ALDHbr fraction, revealed that this fraction was further divided into mesenchymal and epithelial
Summary
Aldehyde dehydrogenase (ALDH) is highly expressed in stem/progenitor cells in various tissues, and cell populations with high ALDH activity (ALDHbr) are associated with tissue repair. MSCs, Takahashi et al Stem Cell Res Ther (2021) 12:471 shown to exhibit pluripotency toward the nonhematopoietic cell lineage, can be isolated from various organs, including the bone marrow, adipose tissue, skeletal muscle, and the umbilical cord [1]. In a mouse model of bleomycin (BLM)-induced lung injury, administration of bone marrow-derived MSCs was reported to improve lung injury by exerting an anti-inflammatory effect [5]. When administered intravenously into the lung, lung SP cell therapy was shown to reduce BLM-induced pulmonary fibrosis and pulmonary arterial hypertension [10]. These results suggest the existence of tissue-specific MSCs in the lung and their involvement in lung injury
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