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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.
Highlights
mesenchymal stem cells (MSC) are plastic adherent cells expressing the minimal marker set of CD90, CD73 and CD105 and absence of CD14, CD79, CD34, CD45, and HLA-DR [1,2]
Smaller oil droplets were observed in WJMSC derived adipocytes as compared to adipocytes derived from bone marrow derived mesenchymal stem cells (BMMSCs) (Figure 1, Figure S1B)
Tumor Necrosis Factor-a (TNFa) primed cells appeared more spindle shaped as compared to the control untreated BMMSCs
Summary
MSCs are plastic adherent cells expressing the minimal marker set of CD90, CD73 and CD105 and absence of CD14, CD79, CD34, CD45, and HLA-DR [1,2]. Bone marrow derived MSCs have been shown to modify or attenuate the effector functions of different immune populations like T cells, B cells, natural killer (NK) cells and dendritic cells (DC) subsets [7,8,9,10,11,12,13] Owing to their property of immune-modulation, MSCs are being considered as double edged sword which can bring about tissue repair and attenuate adverse inflammatory reactions in an allogenic setting. BMMSCs either reverse or prolong survival of mismatched grafts and decrease GVHD [14,15,16,17,18] Despite these reports there are still contradictions in the literature on the immune status of MSCs. Studies by Elippoulous et al, 2005 indicate that allogenic murine MSCs result in robust cell mediated immune responses in MHC class I and class II mismatched immunocompetent mice [19]. The focus of this study is to understand and compare the immune properties of BMMSCs and WJMSCs primed with key pro-inflammatory cytokines, Interferon-c (IFNc) and Tumor Necrosis Factor-a (TNFa)
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