Umbilical cord mesenchymal stem cells enhance the therapeutic effect of imipenem by regulating myeloid-derived suppressor cells in septic mice

Abstract

BACKGROUND: Umbilical cord mesenchymal stem cells (UC-MSCs), which possess potent immunomodulatory effects and low immunogenicity, are considered to be a promising stem cell-based therapy for sepsis. In the current study, we aimed to investigate whether the combined use of UC-MSCs and imipenem has a better effect than imipenem alone in treating Escherichia coli (E. coli)-induced sepsis and to explore the mechanism by which UC-MSCs exert their therapeutic effect in septic mice. METHODS: We randomly divided mice into five groups with 10 mice in each group: the normal control group (control group), the sepsis group (vehicle group), the MSCs treatment group (MSCs group), the imipenem treatment group (imipenem group), and the imipenem plus MSCs treatment group (imipenem + MSCs group). We monitored the survival rate in each group every 12 h for 3 days. After observing the survival rate, another 50 mice were also randomly divided into five groups, and the mice were sacrificed after 24 h. Bacterial colonies from the blood and peritoneal lavage fluid were counted in a blinded manner. Organ injury was analyzed by hematoxylin and eosin (HE) staining. Frequencies of myeloid-derived suppressor cells (MDSCs) in the blood, spleen, and bone marrow (BM) were determined by flow cytometry. Plasma levels of tumor necrosis factor-α (TNF-α), interleukin (IL)-6, IL-1β, and IL-10 were detected by enzyme-linked immunosorbent assay (ELISA). RESULTS: Compared with imipenem treatment, the co-administration of UC-MSCs and imipenem dramatically improved the survival rate, decreased the bacterial load, and ameliorated organ injury. Furthermore, UC-MSCs treatment, either alone or in combination with imipenem, significantly increased plasma levels of IL-10 and the percentage of MDSCs by inducing arginase-1 in septic mice. CONCLUSIONS: Our results indicated that UC-MSCs protect mice against sepsis by acting on MDSCs. Combination therapy of UC-MSCs and imipenem may be a new approach for the future clinical treatment of sepsis.