Mesenchymal stromal cells preserve alveolar macrophages by inducing Sesn2 expression via lactic acid production in a mouse model of bleomycin-induced lung injury

Mesenchymal stromal cells (MSCs) have been shown to exert therapeutic effects by modulating various cell types, including vascular endothelial cells, immune cells, and resident stem cells, at sites of tissue injury. Recent studies have highlighted the importance of MSC-macrophage interactions in suppressing inflammation and promoting tissue regeneration; however, the underlying mechanisms remain poorly understood. In this study, we administered MSCs intratracheally to mice with bleomycin (BLM)-induced lung injury and investigated their effects on alveolar macrophages (AvMs), defined as CD64^High/F4/80^High/Siglecf^High/CD11b^Negative. MSC transplantation alleviated loss of AvMs observed after BLM treatment. Transcriptomic profiling of AvMs revealed increased expression of genes associated with cell survival, oxidative stress resistance, and efferocytosis. Among them, Sesn2 was notably upregulated. <i>Ex vivo</i> experiments using isolated AvMs demonstrated that lactate treatment upregulated both <i>Hypoxia inducible factor 1 alpha</i> (<i>Hif1a</i>) and <i>Sestrin 2</i> (<i>Sesn2</i>), and that siRNA-mediated suppression of <i>Hif1a</i> attenuated the lactic acid-induced increase in <i>Sesn2</i> expression. These findings provide mechanistic insight into how MSCs exert tissue-protective functions via the modulation of tissue-resident macrophages, and identify <i>Sesn2</i> as a key molecule involved in this process. Our study underscores the immunomodulatory capacity of MSCs and their therapeutic relevance in lung injury.