Compact bone mesenchymal stem cells-derived paracrine mediators for cell-free therapy in sepsis

Sepsis, a life-threatening condition resulting in multiple organ dysfunction, is characterized by a dysregulated immune response to infection. Current treatment options are limited, leading to unsatisfactory outcomes for septic patients. Here, we present a series of studies utilizing compact bone mesenchymal stem cells (CB-MSCs) and their derived paracrine mediators, especially exosome (CB-MSCs-Exo), to treat mice with cecal ligation and puncture-induced sepsis. Our results demonstrate that CB-MSCs treatment significantly improves the survival rate of septic mice by mitigating excessive inflammatory response and attenuating sepsis-induced organ injuries. Furthermore, CB-MSCs-conditioned medium, CB-MSCs secretome (CB-MSCs-Sec), and CB-MSCs-Exo exhibit potent anti-inflammatory effects in lipopolysaccharide (LPS)-stimulated murine macrophage (RAW264.7). Intriguingly, intravenous administration of CB-MSCs-Exo confers superior protection against inflammation and organ damage in septic mice compared to CB-MSCs in certain aspects. Using liquid chromatography-tandem mass spectrometry (LC-MS/MS) shotgun proteomic analysis, we identify a range of characterized proteins derived from the paracrine activity of CB-MSCs, involved in critical biological processes such as immunomodulation and apoptosis. Our findings highlight that the paracrine products of CB-MSCs could serve as a promising cell-free therapeutic agent for sepsis. •CB-MSCs possess the potential to mitigate the severity of organ damage and reduce mortality in septic mice.•CB-MSC-Exo retains therapeutic potency akin to their parent cells, and the direct intravascular injection of CB-MSCs-Exo is feasible and safe, supporting further evolution for clinical applications.•The global characterization of the proteome and functional analyses suggest that proteins related to the immune system and inflammation-processes are enriched in CB-MSCs paracrine products, and some specific proteins (prohibitin, SLC25A5, and gelsolin) are enriched in CB-MSCs-Exo, revealing the excellent potential of these proteins in the regulation of sepsis.•The paracrine products of CB-MSCs can serve as a promising cell-free therapeutic agent for sepsis.