Human chorionic membrane mesenchymal stem cell-conditioned medium activates the SOX18/MECP2 axis to protect against...

Sepsis-associated acute lung injury represents a severe complication. It is characterized by an overwhelming inflammatory response and the disruption of pulmonary barrier function, leading to high morbidity and mortality. Despite advances in supportive care, effective therapeutic strategies remain limited. Mesenchymal stem cells derived from the human chorionic membrane, commonly referred to as HCMSCs, represent a highly promising option in the field of regenerative medicine. This is largely owing to their remarkable abilities to modulate the immune system and repair damaged tissues. Nevertheless, the specific biological processes through which these cells exert their influence on lung injury caused by sepsis, especially regarding the modulation of critical molecular signaling pathways, remain to be fully elucidated. A mouse model of sepsis-induced lung injury was established via intraperitoneal lipopolysaccharide (LPS) injection, while human pulmonary microvascular endothelial cells (HPMECs) were stimulated with LPS to mimic an in vitro model. Following the characterization of HCMSCs, the study evaluated their impact on endothelial cell apoptosis, proliferation, and barrier integrity. Inflammatory responses were quantified by measuring key cytokines. To elucidate the molecular mechanism, the study focused on the interaction between the transcription factor SOX18 and MECP2, which was confirmed using chromatin immunoprecipitation and luciferase reporter assays. Finally, the therapeutic efficacy was validated in mice by assessing lung histopathology, edema, and gene/protein expression. Results showed that HCMSCs successfully differentiated into adipocytes and osteoblasts, as confirmed by positive Oil Red O staining and ALP activity. Treatment with HCMSC-conditioned medium (HCMSC^CM) significantly attenuated LPS-induced inhibition of SOX18 expression in HPMECs. LPS-induced HPMEC apoptosis, inflammation, barrier dysfunction and proliferation inhibition were markedly alleviated by HCMSC^CM, as evidenced by reduced apoptosis, decreased IL-6, IL-1β, and TNF-α levels, increased number of EdU-positive cells, and restored expression of tight junction proteins (Occludin and ZO-1) along with TER. However, SOX18 knockdown reversed these protective effects. Mechanistically, SOX18 was found to transcriptionally activate MECP2 in HPMECs. HCMSC^CM effectively mitigated LPS-induced dysfunction in HPMECs through modulation of the SOX18/MECP2 signaling axis. In vivo, HCMSC^CM administration protected against LPS-induced lung injury in mice via regulation of the SOX18/MECP2 axis. In all, HCMSCs exerted protective effects against sepsis-induced lung injury by modulating the SOX18/MECP2 signaling pathway. These findings highlight the therapeutic potential of HCMSCs in treating sepsis-induced lung injury.