Modulation of bone marrow stromal cell functions in infectious diseases by toll-like receptor ligands. J Mol Med

NIH, NIDCR, CSDB, Bethesda, MD 20892, USA.
Journal of Molecular Medicine (Impact Factor: 5.11). 09/2009; 88(1):5-10. DOI: 10.1007/s00109-009-0523-7
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Bone marrow-derived stromal cells (BMSCs, or as they are frequently referred to as mesenchymal stem cells) have been long known to support hematopoiesis and to regenerate bone, cartilage, and adipose tissue. In the last decade, however, a vast amount of data surfaced in the literature to suggest new roles for these cells including tissue regeneration and immunomodulation. A great number of review articles appeared that summarize these new data and focus on different aspects of the physiology of these cells. In this present short review, we will try to summarize the available data based on both mouse and human cells describing how the function of BMSCs might be affected by an infectious environment. These data strongly support the idea that different toll-like receptor ligands can lead to substantial changes in the function of BMSCs that affect their proliferation, apoptosis, migration, and their production and release of immunomodulatory factors.

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Available from: Eva Mezey, Feb 12, 2014
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    • "They express pattern recognition receptors (PRRs) which recognize pathogenic molecules. The PRRs found in hMSCs are Toll like receptors (TLRs) [4]. There are currently 11 known mammalian TLRs of which TLR1-10 are functional in humans [5]. "
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    ABSTRACT: Methicillin-resistant Staphylococcus aureus (MRSA) is the predominant cause of bone infection. Toll like receptors (TLRs) are an important segments of host response to infection and are expressed by a variety of cells including human mesenchymal stem cells (hMSCs). The active form of Vitamin D, 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) has potent immunoregulatory properties, but the mechanism remains poorly understood. The genomic action of 1,25(OH)2D3 is mediated by vitamin D receptor (VDR), hormone-regulated transcription factor. VDR interacts with co-activators and co-repressors are associated with chromatin histone modifications and transcriptional regulation. The aim of our study is to explore MRSA-induced TLRs-mediated pro-inflammatory cytokines expression in hMSCs. Further, we hypothesized that 1,25(OH)2D3 inhibits MRSA-induced cytokines synthesis in hMSCs via inhibition of NF-[cyrillic small letter ka]B transcription factor. Finally, we explored the regulatory role of 1,25(OH)2D3 in MRSA-mediated global epigenetic histone H3 mark, such as, trimethylated histone H3 lysine 9 (H3K9me3), which is linked to gene silencing. Quantitative PCR data revealed that MRSA-infection predominantly induced expression of TLRs 1, 2, 6, NR4A2, and inflammatory cytokines IL-8, IL-6, TNFalpha in hMSCs. MRSA-mediated TLR ligands reduced osteoblast differentiation and increased hMSCs proliferation, indicating the disrupted multipotency function of hMSCs. Pretreatment of 1,25(OH)2D3 followed by MRSA co-culture inhibited nuclear translocation of NF-[cyrillic small letter ka]B-p65, reduced expression of NR4A2 and pro-inflammatory cytokines IL-8, IL-6, and TNFalpha in hMSCs. Further, NF-kappaB-p65, VDR, and NR4A2 were present in the same nuclear protein complex, indicating that VDR is an active part of the nuclear protein complexes for transcriptional regulation. Finally, 1,25(OH)2D3 activated VDR, restores the global level of H3K9me3, to repress MRSA-stimulated inflammatory cytokine IL-8 expression. Pretreatment of 5-dAZA, DNA methylatransferases (Dnmts) inhibitor, dramatically re-expresses 1,25(OH)2D3-MRSA-mediated silenced IL-8 gene. This data indicates that TLR 1, 2, and 6 can be used as markers for localized S. aureus bone infection. 1,25(OH)2D3-VDR may exhibits its anti-inflammatory properties in MRSA-stimulated infection by inhibiting nuclear translocation of NF-kB-p65 and transcripts of IL-8, IL-6, TNFalpha, and NR4A2 in hMSCs. Finally, 1,25(OH)2D3-activated VDR, acting as an epigenetic regulator, inhibits synthesis of cytokines in MRSA-stimulated infection by restoring the global level of H3K9me3, a histone H3 mark for gene silencing.
    BMC Cell Biology 03/2014; 15(1):11. DOI:10.1186/1471-2121-15-11 · 2.34 Impact Factor
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    • "These data suggest that the challenge of the cells with LPS promoted a prompt (within 1 h) increase in the nuclear fraction of NFκB (Figure 1(b), indicated with arrows). The nuclear translocation of (p50)(p65) NFκB is considered to be a part of antiapoptotic response to stress-induced factors [14, 19]. Therefore, preincubation of MSCs with 10 μM PDTC, an inhibitor of the NFκB pathway, suppressed nuclear translocation of (p65) NFκB (Figure 1(c)) that was accompanied by proapoptotic transformations and a loss of cell confluency after application of LPS (Figure 1(d)). "
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    ABSTRACT: Acute bacterial inflammation is accompanied by excessive release of bacterial toxins and production of reactive oxygen and nitrogen species (ROS and RNS), which ultimately results in redox stress. These factors can induce damage to components of tissue barriers, including damage to ubiquitous mesenchymal stromal cells (MSCs), and thus can exacerbate the septic multiple organ dysfunctions. The mechanisms employed by MSCs in order to survive these stress conditions are still poorly understood and require clarification. In this report, we demonstrated that in vitro treatment of MSCs with lipopolysaccharide (LPS) induced inflammatory responses, which included, but not limited to, upregulation of iNOS and release of RNS and ROS. These events triggered in MSCs a cascade of responses driving adaptive remodeling and resistance to a "self-inflicted" oxidative stress. Thus, while MSCs displayed high levels of constitutively present adaptogens, for example, HSP70 and mitochondrial Sirt3, treatment with LPS induced a number of adaptive responses that included induction and nuclear translocation of redox response elements such as NFkB, TRX1, Ref1, Nrf2, FoxO3a, HO1, and activation of autophagy and mitochondrial remodeling. We propose that the above prosurvival pathways activated in MSCs in vitro could be a part of adaptive responses employed by stromal cells under septic conditions.
    Oxidative Medicine and Cellular Longevity 04/2013; 2013(7):186795. DOI:10.1155/2013/186795 · 3.36 Impact Factor
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    • "This idea is supported by experimental and clinical observations indicating that injury can induce recruitment of mesenchymal stromal cells (MSCs) from bone marrow and promote their proliferative activity in order to re-constitute integrity of fractured tissue and mediate natural debridement [2] [5] [14] [15]. Moreover, it has been shown recently that transplanted MSCs can suppress experi‐ mental sepsis and can promote healing of radiation-induced cutaneous injury and survival from acute radiation syndrome [16] [17] [18] [19] [20]. All of this evidence suggests that MSCs play a crucial role in mitigation of systemic and local effects of tissue injury under different pathophysio‐ logical conditions. "
    Autophagy - A Double-Edged Sword - Cell Survival or Death?, 1 edited by Yannick Bailly, 04/2013: chapter 16: pages 331-350; InTech. Rijeka (, ISBN: ISBN 978-953-51-1062-0
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