CXCR5-engineered mesenchymal stromal cells home to spleen and mitigate post-sepsis syndrome by preventing secondary...

Sepsis survivors frequently develop compromised humoral immunity, manifesting as prolonged immunosuppression that increases susceptibility to secondary infections with high associated mortality. While mesenchymal stromal cells (MSCs) have demonstrated efficacy in mitigating initial inflammatory responses and improving early survival rates in murine cecal ligation and puncture (CLP) models, they show limited effectiveness against subsequent secondary infections. Given that lymphopenia represents a primary driver of this infection vulnerability, we sought to investigate whether spleen-targeted MSC therapy could prevent lymphocyte depletion and enhance protection against secondary infections.

In this study, we developed CXCR5-overexpressing MSCs (MSC^CXCR5) to enhance their targeted migration toward splenic CXCL13. Using a CLP mouse model followed by secondary Staphylococcus aureus (S. aureus) infection, we systematically evaluated the therapeutic potential of MSC^CXCR5 in combating post-sepsis immunosuppression.

MSC^CXCR5 demonstrated enhanced splenic migration, specifically homing to CXCL13-rich B-cell zones, and conferred significant protection against both S. aureus secondary infection and sepsis-induced lymphopenia. Mechanistic investigations revealed that MSC^CXCR5 treatment preserved follicular and germinal center B-cell populations, maintaining splenic architecture and potentiating antigen-specific B-cell responses to CLP challenge. These effects collectively contributed to markedly improved survival outcomes in CLP mice following secondary infection.

Our findings demonstrate that MSC^CXCR5 confers dual-phase protection in sepsis, improving survival during both the initial hyperinflammatory phase and subsequent immunosuppressive period. This comprehensive therapeutic effect stems from MSC^CXCR5's ability to preserve B-cell function and prevent secondary infections in septic mice.