Pro-Inflammatory Cytokines, IFNγ and TNFα, Influence Immune Properties of Human Bone Marrow and Wharton Jelly Mesenchymal Stem Cells Differentially

Abstract

BackgroundWharton's jelly derived stem cells (WJMSCs) are gaining attention as a possible clinical alternative to bone marrow derived mesenchymal stem cells (BMMSCs) owing to better accessibility, higher expansion potential and low immunogenicity. Usage of allogenic mesenchymal stem cells (MSC) could be permissible in vivo only if they retain their immune properties in an inflammatory setting. Thus the focus of this study is to understand and compare the immune properties of BMMSCs and WJMSCs primed with key pro-inflammatory cytokines, Interferon-γ (IFNγ) and Tumor Necrosis Factor-α (TNFα).Methodology/Principal FindingsInitially the effect of priming on MSC mediated suppression of alloantigen and mitogen induced lymphoproliferation was evaluated in vitro. Treatment with IFNγ or TNFα, did not ablate the immune-suppression caused by both the MSCs. Extent of immune-suppression was more with WJMSCs than BMMSCs in both the cases. Surprisingly, priming BMMSCs enhanced suppression of mitogen driven lymphoproliferation only; whereas IFNγ primed WJMSCs were better suppressors of MLRs. Further, kinetic analysis of cytokine profiles in co-cultures of primed/unprimed MSCs and Phytohematoagglutinin (PHA) activated lymphocytes was evaluated. Results indicated a decrease in levels of pro-inflammatory cytokines. Interestingly, a change in kinetics and thresholds of Interleukin-2 (IL-2) secretion was observed only with BMMSCs. Analysis of activation markers on PHA-stimulated lymphocytes indicated different expression patterns in co-cultures of primed/unprimed WJMSCs and BMMSCs. Strikingly, co-culture with WJMSCs resulted in an early activation of a negative co-stimulatory molecule, CTLA4, which was not evident with BMMSCs. A screen for immune suppressive factors in primed/unprimed WJMSCs and BMMSCs indicated inherent differences in IFNγ inducible Indoleamine 2, 3-dioxygenase (IDO) activity, Hepatocyte growth factor (HGF) and Prostaglandin E-2 (PGE2) levels which could possibly influence the mechanism of immune-modulation.Conclusion/SignificanceThis study demonstrates that inflammation affects the immune properties of MSCs distinctly. Importantly different tissue derived MSCs could utilize unique mechanisms of immune-modulation.

Cord-Blood-Derived Mesenchymal Stromal Cells Downmodulate CD4+T-Cell Activation by Inducing IL-10-Producing Th1 Cells

“…Based on our data, we cannot confirm that the observed IFNg + IL-10 + double-positive subpopulation is generated from a switched Th1 population, since we cannot trace single T-cell clones, and alternatively, the same cellular distribution could be due to Th1 cell death or either a cell survival advantage or selective expansion of IL-10-producing cells. Our observation that the major induction by MSCs of this particular T-cell phenotype occurred in the presence of allogeneic antigen-presenting cells is evidence for the commonly accepted notion that a proinflammatory environment favors the suppressive function of MSCs (the so-called licensing process) both in vivo and in vitro [31][32][33].…”

The Regenerative Medicine Laboratory: Facilitating Stem Cell Therapy for Equine Disease

“…These inherent differences appear to be further enhanced by inflammation. These transcriptome studies are compatible with in vitro tissue source comparison studies [22][23][24] that find baseline and activated MSCs from BM, cord tissue, and ASC modulate the immune response and respond to inflammatory mediators distinctly [5,25]. Although research with MSCs from different tissue sources in horses is just beginning, equine MSCs appear to be remarkably similar to other species described to date.…”

Mesenchymal Stem Cell Therapy Protects Lungs from Radiation-Induced Endothelial Cell Loss by Restoring Superoxide Dismutase 1 Expression

“…Our data might suggest that BM-MSCs have a weaker response overall and in particular for the radioprotection of vascular EC. Affirmative, earlier reports already suggested that BM-MSCs were less effective for MSC therapy compared to other stem cell sources, for example, compared to adipose tissue-derived or fetal MSCs (64,66,86).…”