Antibacterial fusion protein BPI21/LL-37 modification enhances the therapeutic efficacy of human umbilical cord mesenchymal stem cells in sepsis

Abstract Sepsis is potentially a life-threatening condition and a major cause of death in the intensive care units (ICUs), which is characterized by multiple organ dysfunctions as a result of unbalanced host inflammatory response to pathogens. However, effective treatment or intervention to prevent sepsis-associated lethality is still lacking. Human umbilical cord mesenchymal stem cells (hUC-MSCs) transplantation has been shown to have potent immunomodulatory properties and improve tissue repair, yet lacking direct antibacterial and endotoxin clearance activities. In this study, we engineered hUC-MSCs to express a broad-spectrum antibacterial fusion peptide containing BPI21 and LL-37 (named BPI21/LL-37), and confirmed that the BPI21/LL-37 modification did not affect the stemness and immunoregulatory capacities of hUC-MSCs, but remarkably enhanced its antibacterial and toxin-neutralizing activities in vitro. Furthermore, we showed that administration of BPI21/LL-37-engineered hUC-MSCs significantly reduces serum levels of TNF-α, IL-1β and IL-6 while increases that of IL-10 in cecal ligation and puncture (CLP)-induced sepsis mouse model. Administration of BPI21/LL-37-engineered hUC-MSCs significantly reduced systemic endotoxin (LPS) levels and organ bacterial load, ameliorated damage to multiple organs, and improved survival. Taken together, our study demonstrates that BPI21/LL-37-engineered hUC-MSCs might offer a novel therapeutic strategy to prevent or treat sepsis via enhanced antimicrobial and anti-inflammatory properties to better preserve organ functions.