Tseng, P. | bioRxiv Science

bioRxiv2025

Lung derived extracellular vesicles have distinct pro-repair effects, depending on the age of their source tissue

Many age-related lung diseases encompass aberrant repair mechanisms. To develop novel treatments for these diseases, it is critical to understand how biology and repair signals are altered in aged lungs. Extracellular vesicles (EVs) carry bioactive signals reflecting their source tissue; therefore, we used EVs derived from precision-cut lung slices (PCLS) as tools to investigate differences in lung biology and repair signals that occur upon ageing and injury. We compared the physicochemical properties and biological content of four groups of EVs, obtained from uninjured and injured, young and aged PCLS. Treatment with EVs obtained from young, uninjured (YU) PCLS decreased apoptotic cells in both young and aged spatially injured (AIR)-PCLS. YU EVs also increased the percentage of alveolar progenitor cells in aged AIR-PCLS, indicating that aged lungs retain the capacity to mount a repair response, if provided with the right biological cues. Small RNA sequencing revealed the miRNA content of each EV group is altered, depending on the physiological conditions of their source tissue. Bioinformatic analysis of the target genes regulated by differentially expressed miRNAs identified enrichment of genes required for lung development and repair. These findings pave the way for future therapeutic strategies to repair or regenerate aged lungs.

cell biology↗

bioRxiv2025

Targeting serine dehydratase supports amino acid homeostasis and skin repair

Serine and glycine are altered in patients with metabolic disorders, and this dysregulation can lead to diverse pathologies1-6. Modulation of serine levels via diet can influence relevant phenotypes in mouse models of metabolic syndrome7,8. Here we identify serine dehydratase (Sds), a gluconeogenic hepatic enzyme involved in serine and threonine catabolism, as a key regulator of systemic serine and sphingolipid metabolism. We show that SDS is expressed and active in human liver tissue. Furthermore, Sds abundance strongly correlates with hepatic serine. This enzyme is highly active in BKS-db/db mice, which show amino acid alterations reminiscent of type 2 diabetes. Hepatic Sds overexpression increases serine and threonine degradation and promotes the accumulation of toxic 1-deoxysphingolipids (doxSLs). Conversely, Sds deletion dramatically increases systemic serine, glycine, and threonine while altering canonical and non-canonical sphingolipids. Finally, Sds deletion in BKS-db/db mice reduces skin doxSLs and accelerates wound healing. Our results demonstrate that Sds constrains serine levels in circulation and suggest therapeutic approaches for targeting this enzyme to improve chronic disorders.

physiology↗