BMSCs pre-treatment ameliorates inflammation-related tissue destruction in LPS-induced rat DIC model

Biao Wang,Shuming Wu,Tao Wang,Changyong Yang,Zengshan Ma

doi:10.1038/s41419-018-1060-5

Abstract

This study aimed to investigate the effect of bone marrow-derived mesenchymal stem cells (BMSCs) on disseminated intravascular coagulation (DIC) model rats and to further explore the underlying mechanism. A rat model of lipopolysaccharide (LPS)-induced DIC was successfully established, as indicated by impaired plasma hemostatic parameters and damaged organ functions in rats. Importantly, pre-treatment with rat allogeneic BMSCs before LPS injection significantly alleviated systemic intravascular coagulation, reduced plasma levels of organ dysfunction indicators and pro-inflammatory cytokines, suppressed fibrin microthrombi formation, ameliorated liver, heart, and renal injuries, and increased 24-hour survival rates in LPS-induced DIC rats. The protection of BMSCs against DIC was in a moderately dose-dependent manner. Further investigation revealed that BMSCs co-cultured with peripheral blood mononuclear cells (PBMCs) significantly inhibited the LPS-stimulated PBMCs proliferation and the release of pro-inflammatory cytokines from PBMCs. Of note, upregulation of immunosuppressive factors including indoleamine 2,3-dioxygenase and interleukin-10, which was induced by interferon-γ, contributed to BMSCs-mediated inhibition of LPS-stimulated PBMCs proliferation. These effects do not depend on the direct cell–cell contact. In conclusion, BMSCs pre-treatment ameliorates inflammation-related tissue destruction in LPS-induced DIC model rats. The protection of BMSCs may be attributed to their anti-inflammatory and immunomodulatory properties, which render BMSCs a promising source for stem cell-based therapeutic approaches in inflammation-related DIC.

Highlights

Disseminated intravascular coagulation (DIC) is a devastating clinical condition caused by unbalanced activation between coagulation and fibrinolysis[1]
When exposed to an adipogenic stimulus, the cells displayed an adipocyte phenotype and accumulation of neutral lipid droplets in the cytoplasm (Supplementary Figure 1F). These results indicated that the obtained bone marrow-derived microcirculationMesenchymal stem cells (MSCs) (BMSCs) conformed to the well-established criteria
We found that the suppressive activity of BMSCs on peripheral blood mononuclear cells (PBMCs) proliferation was abrogated by blocking IL-10 and IDO but not transforming growth factor β1 (TGF-β1), inducible nitric oxide synthase (iNOS), or COX2, both under both cell–cell contact and Transwell conditions with LPS stimulation

Summary

Introduction

Disseminated intravascular coagulation (DIC) is a devastating clinical condition caused by unbalanced activation between coagulation and fibrinolysis[1]. The unique immunomodulatory and antiinflammatory effects of MSCs have been demonstrated in several animal disease models related to inflammation, such as bowel disease[18], periodontitis[21], and sepsis[22]. Taken together, these observations have provided convincing evidence that BMSCs-based therapy may be potential for the treatment of DIC

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