iPSC Exosomes Rejuvenate Senescent Basal Stem Cells via YBX1-NFYB Axis

Senescence of somatic stem cells contributes substantially to the pathogenesis of diverse degenerative diseases. Idiopathic pulmonary fibrosis (IPF), for instance, is closely linked to senescence of KRT5+ basal stem cells. Here, we show that exosomes derived from induced pluripotent stem cells exhibiting elevated stemness can reverse the senescent phenotypes of KRT5+ basal cells isolated from IPF patients, enhancing their migration, proliferation, and differentiation under stress conditions while expanding the stem cell pool. In mouse models of aging and injury, these exosomes demonstrate remarkable anti-senescence effects in KRT5+ basal stem cells and enhance their proliferative and differentiative capacities. Mechanistic analyses indicate that these modulations are highly associated with the YBX1-NFYB signaling axis, which governs senescence and regenerative capacity in tissue-resident basal stem cells. Collectively, these results demonstrate that exosomes from stem cells with robust stemness can activate and restore function in cells with diminished stemness, providing a promising strategy for tissue regeneration and amelioration of age-associated pathologies.