Department of Molecular and Internal Medicine, Graduate School of Biomedical & Health Sciences, Hiroshima University, 1-2-3, Kasumi, Minami-ku, Hiroshima, 734-8551, Japan.
Department of Physical Analysis and Therapeutic Sciences, Graduate School of Biomedical & Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan.
Stem Cell Res Ther. 2024 Sep 15;15(1):304. doi: 10.1186/s13287-024-03933-8.
Although bone marrow-derived cells with high aldehyde dehydrogenase activity (ALDH) have shown therapeutic potential against various diseases in animal studies, clinical trials have failed to show concurrent findings. We aimed to clarify the optimal conditions for the efficacy of ALDH cells by using a murine bleomycin-induced pulmonary fibrosis model.
We intravenously transferred male or female donor C57BL/6 mice-derived ALDH cells into recipient C57BL/6 mice under various conditions, and used mCherry-expressing mice as a donor to trace the transferred ALDH cells.
Pulmonary fibrosis improved significantly when (1) female-derived, not male-derived, and (2) lineage (Lin)-negative, not lineage-positive, ALDH cells were transferred during the (3) fibrotic, not inflammatory, phase. Consistent with the RNA-sequencing results, female-derived Lin/ALDH cells were more resistant to oxidative stress than male-derived cells in vitro, and transferred female-derived Lin/ALDH cells were more viable than male-derived cells in the fibrotic lung. The mechanism underlying the antifibrotic effects of Lin/ALDH cells was strongly associated with reduction of oxidative stress.
Our results indicated that Lin/ALDH cell therapy could ameliorate pulmonary fibrosis by reducing oxidative stress and suggested that their efficacy was mediated by sex-related differences. Thus, sex-awareness strategies may be important for clinical application of bone marrow ALDH cells as a therapeutic tool.
虽然骨髓来源的高醛脱氢酶活性（ALDH）细胞在动物研究中显示出对各种疾病的治疗潜力，但临床试验并未显示出一致的结果。我们旨在通过使用小鼠博来霉素诱导的肺纤维化模型来阐明 ALDH 细胞疗效的最佳条件。
我们在各种条件下将雄性或雌性供体 C57BL/6 小鼠来源的 ALDH 细胞静脉转移到受体 C57BL/6 小鼠中，并使用表达 mCherry 的小鼠作为供体来追踪转移的 ALDH 细胞。
当（1）雌性来源，而不是雄性来源，和（2）谱系（Lin）阴性，而不是 Lin 阳性的 ALDH 细胞在（3）纤维化而不是炎症阶段转移时，肺纤维化显著改善。与 RNA 测序结果一致，体外雌性来源的 Lin/ALDH 细胞比雄性来源的细胞更能抵抗氧化应激，并且在纤维化的肺中，转移的雌性来源的 Lin/ALDH 细胞比雄性来源的细胞更具活力。Lin/ALDH 细胞的抗纤维化作用的机制与减少氧化应激密切相关。
我们的结果表明，Lin/ALDH 细胞治疗可以通过减少氧化应激来改善肺纤维化，并表明其疗效是由性别相关差异介导的。因此，对于将骨髓 ALDH 细胞作为治疗工具的临床应用，性别意识策略可能很重要。
