Abstract
Human umbilical cord mesenchymal stromal cells (hUC-MSCs) are currently being used as novel therapeutic agents in numerous clinical trials. Previous works have shown that hUC-MSCs possess profound immunomodulatory capacities through IL-1 stimulation produced by peripheral blood mononuclear cells (PBMCs), their main cellular partner in most pathophysiological and therapeutic situations. The present study was designed to explore the role of TNF-α in these interactions. In these experiments, we demonstrated that TNF-α originated from PBMCs under the influence of IL-1. We also showed that TNF-α acted differently depending upon the concentrations reached. At low concentrations it clearly contributed to IL-6 and monocyte chemotactic protein 1 (MCP-1) production. At high concentrations, used alone or in association with the TNF-related apoptosis-inducing ligand, TNF-α also stimulated hUC-MSC IL-6 but, more intensely, MCP-1 production. This stimulation was associated but independent of apoptosis induction in a process involving Inhibitor of Apoptosis Proteins. Interferon gamma (IFN-γ), tested to stimulate PBMC and tissue activation, amplified IL-6 and MCP-1 production and cell death by, apparently, a different process involving necrosis. Our findings bring new insights into the complex interactions between hUC-MSCs and PBMCs, involving cytokines, chemokines and cell death, and are of fundamental importance for tissue homeostasis.
Highlights
Mesenchymal stem cells, better denoted as multipotent mesenchymal stromal cells (MSCs) [1], are the focus of intense efforts at elucidating their nature and unique properties as well as PLOS ONE | DOI:10.1371/journal.pone.0128647 May 29, 2015TNF-α and Cell Death in MSC/peripheral blood mononuclear cells (PBMCs) Interactions
In high concentrations, TNF-α stimulated hUC-MSC production of IL-6 but, to a greater extent, monocyte chemotactic protein 1 (MCP-1) that could be associated with induction of cell death in a process involving Inhibitor of Apoptosis Proteins (IAPs) but independent of the cell death itself
TNF-α was not detected in hUC-MSC SN neither in basal nor IL-1 stimulated conditions but could be detected in PBMC SN, suggesting that TNF-α originated from PBMCs in parallel with IL-1ß production
Summary
Mesenchymal stem cells, better denoted as multipotent mesenchymal stromal cells (MSCs) [1], are the focus of intense efforts at elucidating their nature and unique properties as well as PLOS ONE | DOI:10.1371/journal.pone.0128647 May 29, 2015. Human umbilical-cord-derived mesenchymal stromal cells (hUC-MSCs), which can be isolated and expanded in large quantities in vitro, are being explored as promising candidates for potential clinical applications [6, 7]. In high concentrations, TNF-α stimulated hUC-MSC production of IL-6 but, to a greater extent, MCP-1 that could be associated with induction of cell death in a process involving Inhibitor of Apoptosis Proteins (IAPs) but independent of the cell death itself. This effect was increased by the presence of TNF-related apoptosis-inducing ligand (TRAIL) and INF-γ
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