Mesenchymal stem/stromal cells as a therapeutic for sepsis: a review on where do we stand?

Abstract

Sepsis is one of the leading causes of morbidity and mortality in the United States and Worldwide despite advances in quick recognition and early antibiotics, fluids, and vasopressors. Mesenchymal stem/stromal cells (MSCs) have gained attention as a biologic therapy given their unique anti-inflammatory, immunomodulatory, and anti-bacterial characteristics. MSCs have had success in treating a range of diseases, however limited clinical trials exist specifically for MSC use in sepsis. This article reviews the properties of MSCs that make them favorable for treating sepsis, as well as the current state of clinical trials. All clinical trials presented here demonstrated MSC safety, with a mixture of efficacy results and a heterogeneity of trial methods. Ultimately, MSCs are a promising novel therapeutic for sepsis, however a consensus in cell source, dosage, preparation, and delivery needs to be further investigated for MSCs to transition from bench to bedside and become a true therapeutic for sepsis.

Keywords: Clinical trials; MSC; Mesenchymal stem cells; Sepsis; Septic shock.

Fig. 1

Unique properties of mesenchymal stem cells (MSCs) that make them applicable for therapeutic use in sepsis. MSCs exhibit dynamic anti-inflammatory, immunomodulatory, and anti-bacterial properties that work synchronously. Their anti-inflammatory properties rely on the expression of tumor necrosis factor receptor (TNFR), toll-like receptor 3 (TLR3) and the secretion of interleukin-4 (IL-4), interleukin-6 (IL-6), interleukin-10 (IL-10), indoleamine 2,3-dioxygenase (IDO), tumor necrosis factor-stimulated gene-6 (TSG-6), transforming growth factor beta (TGF-β), prostaglandin E2 (PGE2), and interleukin 1 receptor antagonist (IL-1ra). Their immunomodulatory properties rely on the inhibition of dendritic cells (DCs), natural killer (NK) cells, CD4 + T helper (Th) cells, CD8 + cytotoxic T cells (CTLs), inhibition and stimulation of B cells, stimulation of macrophages and T regulatory (Treg) cells. Specifically, inhibition of NK cells results in inhibition of cytotoxicity and alteration in production and secretion of IL-6, IL-10, Interferon gamma (IFN-γ), and tumor necrosis factor alpha (TNF-α). Their anti-bacterial properties rely on the expression of IDO and interleukin-17 (IL-17) and the secretion of antimicrobial peptides (AMPs) including human -defensin-2, hepcidin, LL-37, and liocalin-2