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. 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. The 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. Lung 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. Our 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.

中文翻译：

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具有高醛脱氢酶活性的肺驻留祖细胞的抗纤维化作用

醛脱氢酶（ALDH）在各种组织的干/祖细胞中高表达，具有高ALDH活性（ALDHbr）的细胞群与组织修复有关。然而，对肺常驻 ALDHbr 知之甚少。进行这项研究是为了阐明肺驻留 ALDHbr 细胞的特征，并使用博莱霉素诱导的肺纤维化小鼠模型评估它们作为细胞治疗工具的可能用途。在对照 C57BL/6 小鼠中评估肺驻留/非造血 (CD45-) ALDHbr 细胞的特征。在博来霉素诱导的肺纤维化中研究了 CD45-/ALDHbr 在细胞治疗中的动力学和潜在用途。使用表达 mCherry 的小鼠作为供体确定转移的 CD45-/ALDHbr 细胞的定位。还使用老年小鼠评估了衰老对 ALDH 表达的影响。与具有低 ALDH 活性的细胞群相比，肺 CD45-/ALDHbr 显示出更高的增殖和集落形成潜力。在博来霉素诱导的肺纤维化过程中，CD45-/ALDHbr 细胞群，尤其是其 CD45-/ALDHbr/PDGFRα+ 亚群，在肺中显着减少。此外，ALDH 亚型的 mRNA 表达在纤维化肺中显着降低。当体内转移到博莱霉素预处理的小鼠体内时，CD45-/ALDHbr 细胞到达损伤部位，改善肺纤维化，恢复 ALDH mRNA 的降低表达，延长生存期，这与视黄醇代谢途径的上调和抑制促纤维化细胞因子。CD45-/ALDHbr/PDGFRα+ 群体的减少在老年小鼠中比在年轻小鼠中更为显着。我们的结果强烈表明 ALDH 和肺驻留 CD45-/ALDHbr 细胞的肺表达与肺纤维化有关。目前的研究表明 CD45-/ALDHbr 细胞有可能在肺纤维化治疗中作为新型有用的细胞治疗工具得到应用。