Sex-related differences in efficacy of bone marrow-derived high aldehyde dehydrogenase activity cells against pulmonary fibrosis.

BACKGROUND

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.

METHODS

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.

RESULTS

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.

CONCLUSIONS

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.