Umbilical Cord-Derived CD362+ Mesenchymal Stromal Cells Attenuate Polymicrobial Sepsis Induced by Caecal Ligation and Puncture.

Hector Gonzalez,John G Laffey,Michael Scully,Colm Keane,Shahd Horie,Claire H Masterson,Brendan D Higgins,Daniel O’Toole,Stephen J Elliman

doi:10.3390/ijms21218270

Abstract

Mesenchymal stromal cells (MSCs) have a multimodal, immunomodulatory mechanism of action and are now in clinical trials for single organ and systemic sepsis. However, a number of practicalities around source, homogeneity and therapeutic window remain to be determined. Here, we utilised conditioned medium from CD362+-sorted umbilical cord-human MSCs (UC-hMSCs) for a series of in vitro anti-inflammatory assays and the cryopreserved MSCs themselves in a severe (Series 1) or moderate (Series 2+3) caecal ligation and puncture (CLP) rodent model. Surviving animals were assessed at 48 h post injury induction. MSCs improved human lung, colonic and kidney epithelial cell survival following cytokine activation. In severe systemic sepsis, MSCs administered at 30 min enhanced survival (Series 1), and reduced organ bacterial load. In moderate systemic sepsis (Series 2), MSCs were ineffective when delivered immediately or 24 h later. Of importance, MSCs delivered 4 h post induction of moderate sepsis (Series 3) were effective, improving serum lactate, enhancing bacterial clearance from tissues, reducing pro-inflammatory cytokine concentrations and increasing antimicrobial peptides in serum. While demonstrating benefit and immunomodulation in systemic sepsis, therapeutic efficacy may be limited to a specific point of disease onset, and repeat dosing, MSC enhancement or other contingencies may be necessary.

Highlights

Sepsis is a life-threatening syndrome caused by bacterial infection [1] in which patients develop an inflammatory response to a pathogen, producing shock and organ damage that can lead to death with an overall mortality rate of 40% [2]
Conditioned media derived from CD362+ UC-Mesenchymal stromal cells (MSCs) culture significantly attenuated cytomix-induced nuclear factor kappa B (NF-κB) activation in type II alveolar A549 cells compared with vehicle control (Figure 1A), indicating an anti-inflammatory effect in a sepsis-relevant tissue type
CD362+ UC-MSC-conditioned medium (CM) improved cell viability in kidney-derived HK2 cells (Figure 1E) and gut-derived T84 cells (Figure 1F) after cytomix stimulation compared with vehicle control, suggesting a direct supportive effect of MSC in organ failure

Summary

Introduction

Sepsis is a life-threatening syndrome caused by bacterial infection [1] in which patients develop an inflammatory response to a pathogen, producing shock and organ damage that can lead to death with an overall mortality rate of 40% [2]. The inflammatory reaction is a result of the generation of diverse pro-inflammatory molecules including tumour necrosis factor (TNF)-α, interleukin (IL)-1β, IL-2, IL-6, IL-8 and interferon (IFN)-γ. This “cytokine storm” is responsible for early sepsis-related multiple organ failure and death [3]. Our previous research has shown that bone-marrow-derived MSCs enhance the resolution of E. coli pneumonic sepsis [10] and ventilator-induced lung injury (VILI) animal models [11]. There are ongoing clinical trials investigating the beneficial effect of MSCs in sepsis patients (NCT03369275, NCT02883803)

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Discussion

Conclusion