Antibacterial Fusion Protein BPI21/LL-37 Modification Enhances the Therapeutic Efficacy of hUC-MSCs in Sepsis.
Mol Ther
; 28(8): 1806-1817, 2020 08 05.
Article
em En
| MEDLINE
| ID: mdl-32445625
ABSTRACT
Sepsis, which is characterized by multiple organ dysfunctions as a result of an unbalanced host-inflammatory response to pathogens, is potentially a life-threatening condition and a major cause of death in the intensive care units (ICUs). However, effective treatment or intervention to prevent sepsis-associated lethality is still lacking. Human umbilical cord mesenchymal stem cell (hUC-MSC) transplantation has been shown to have potent immunomodulatory properties and improve tissue repair yet lacks 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 tumor necrosis factor α (TNF-α), interleukin 1ß (IL-1ß), and IL-6, whereas 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 (lipopolysaccharide [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 preserve organ functions better.
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Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Cordão Umbilical
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Proteínas Recombinantes de Fusão
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Sepse
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Peptídeos Catiônicos Antimicrobianos
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Transplante de Células-Tronco Mesenquimais
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Células-Tronco Mesenquimais
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Antibacterianos
Tipo de estudo:
Etiology_studies
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Prognostic_studies
Limite:
Animals
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Humans
Idioma:
En
Ano de publicação:
2020
Tipo de documento:
Article