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• W2000229809 abstract "Recent observations have demonstrated that one of the functions of mesenchymal stem/stromal cells (MSCs) is to serve as guardians against excessive inflammatory responses. One mode of action of the cells is that they are activated to express the interleukin (IL)-1 receptor antagonist. A second mode of action is to create a negative feedback loop in which tumor necrosis factor-α (TNF-α) and other proinflammatory cytokines from resident macrophages activate MSCs to secrete the multifunctional anti-inflammatory protein TNF-α stimulated gene/protein 6 (TSG-6). The TSG-6 then reduces nuclear factor-κB (NF-κB) signaling in the resident macrophages and thereby modulates the cascade of proinflammatory cytokines. A third mode of action is to create a second negative feedback loop whereby lipopolysaccharide, TNF-α, nitric oxide, and perhaps other damage-associated molecular patterns (DAMPs) from injured tissues and macrophages activate MSCs to secrete prostaglandin E2 (PGE2). The PGE2 converts macrophages to the phenotype that secretes IL-10. There are also suggestions that MSCs may produce anti-inflammatory effects through additional modes of action including activation to express the antireactive oxygen species protein stanniocalcin-1. Recent observations have demonstrated that one of the functions of mesenchymal stem/stromal cells (MSCs) is to serve as guardians against excessive inflammatory responses. One mode of action of the cells is that they are activated to express the interleukin (IL)-1 receptor antagonist. A second mode of action is to create a negative feedback loop in which tumor necrosis factor-α (TNF-α) and other proinflammatory cytokines from resident macrophages activate MSCs to secrete the multifunctional anti-inflammatory protein TNF-α stimulated gene/protein 6 (TSG-6). The TSG-6 then reduces nuclear factor-κB (NF-κB) signaling in the resident macrophages and thereby modulates the cascade of proinflammatory cytokines. A third mode of action is to create a second negative feedback loop whereby lipopolysaccharide, TNF-α, nitric oxide, and perhaps other damage-associated molecular patterns (DAMPs) from injured tissues and macrophages activate MSCs to secrete prostaglandin E2 (PGE2). The PGE2 converts macrophages to the phenotype that secretes IL-10. There are also suggestions that MSCs may produce anti-inflammatory effects through additional modes of action including activation to express the antireactive oxygen species protein stanniocalcin-1. We and other vertebrates are equipped to live in a sea of microorganisms. The reason we survive is because we have formidable inflammatory and immune response systems to protect us against both external confrontations with microorganisms and internal confrontations with the bacteria in our intestinal flora that outnumber the cells in our bodies.1Berg RD The indigenous gastrointestinal microflora.Trends Microbiol. 1996; 4: 430-435Abstract Full Text PDF PubMed Scopus (853) Google Scholar,2Savage DC Microbial ecology of the gastrointestinal tract.Annu Rev Microbiol. 1977; 31: 107-133Crossref PubMed Scopus (1667) Google Scholar However, the same systems need multiple checks to protect us against excessive inflammatory and immune responses. In fact, there is an increasing realization that excessive or nonresolving inflammation makes a major contribution to the damage wrought by diseases such as obesity, diabetes, myocardial infarction (MI), stroke, parkinsonism, and Alzheimer's disease.3Nathan C Ding A Nonresolving inflammation.Cell. 2010; 140: 871-882Abstract Full Text Full Text PDF PubMed Scopus (1416) Google Scholar,4Chen GY Nuñez G Sterile inflammation: sensing and reacting to damage.Nat Rev Immunol. 2010; 10: 826-837Crossref PubMed Scopus (2045) Google Scholar Fortunately, we have multiple systems for resolving and modulating inflammation. The systems include small molecules such as prostaglandins, lipoxins, protectins, and resolvins.5Serhan CN Chiang N Van Dyke TE Resolving inflammation: dual anti-inflammatory and pro-resolution lipid mediators.Nat Rev Immunol. 2008; 8: 349-361Crossref PubMed Scopus (2200) Google Scholar They also include cellular phenotypes such as alternatively activated M2 macrophages6Gordon S Martinez FO Alternative activation of macrophages: mechanism and functions.Immunity. 2010; 32: 593-604Abstract Full Text Full Text PDF PubMed Scopus (2799) Google Scholar and regulatory T cells.7Izcue A Coombes JL Powrie F Regulatory lymphocytes and intestinal inflammation.Annu Rev Immunol. 2009; 27: 313-338Crossref PubMed Scopus (408) Google Scholar,8Wan YY Regulatory T cells: immune suppression and beyond.Cell Mol Immunol. 2010; 7: 204-210Crossref PubMed Scopus (60) Google Scholar Recent reports indicate that additional important guardian cells for modulating inflammation are mesenchymal stem/stromal cells (MSCs). The interest in the guardian role of MSCs is in part related to their presence as adventitial reticular cells9Bianco P Sacchetti B Riminucci M Osteoprogenitors and the hematopoietic microenvironment.Best Pract Res Clin Haematol. 2011; 24: 37-47Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar that participate in normal wound repair and in regulation of hematopoietic cells in bone marrow.10Méndez-Ferrer S Michurina TV Ferraro F Mazloom AR Macarthur BD Lira SA et al.Mesenchymal and haematopoietic stem cells form a unique bone marrow niche.Nature. 2010; 466: 829-834Crossref PubMed Scopus (2468) Google Scholar The interest in MSCs has been further enhanced by their potential use for therapies of various diseases, because the cells can be readily obtained from patients, they are easily expanded in culture, and they are generally not tumorigenic. Recent reports have demonstrated that many, but not all, of the therapeutic effects of the cells seen in animal models are explained by MSCs being activated by signals from injured tissues to secrete anti-inflammatory factors. In some instances, direct administration of the same factors replicates the anti-inflammatory effects of the MSCs. Therefore, the factors secreted by activated MSCs may replace the use of the cells for some therapeutic applications. The role of MSCs as guardians of inflammation has gradually emerged from research on the cells over the past several decades. The evolving data have prompted dramatic shifts in the hypotheses or paradigms for the research.11Prockop DJ Kota DJ Bazhanov N Reger RL Evolving paradigms for repair of tissues by adult stem/progenitor cells (MSCs).J Cell Mol Med. 2010; 14: 2190-2199Crossref PubMed Scopus (216) Google Scholar Initially, the cells were explored as feeder layers that provided a niche for culture of hematopoietic cells (paradigm I). Then the cells were explored as reparative cells that can engraft in injured tissues and differentiate to replace damaged cells (paradigm II). More recently, the data demonstrate that the cells only transiently appear in injured tissues under most conditions, but during their brief appearance they respond to crosstalk with injured cells to limit tissue destruction or enhance repair by a variety of mechanisms (paradigm III). The mechanisms include (a) upregulation of genes that modulate excessive inflammatory and immune reactions; (b) providing a niche to enhance proliferation and differentiation of tissue-endogenous stem/progenitor cells (as in paradigm I); and (c) transfer of vesicular components that contain mitochondria and microRNAs. The role of MSCs as guardians of inflammation became more apparent as the events initiating inflammation have been defined in greater detail.4Chen GY Nuñez G Sterile inflammation: sensing and reacting to damage.Nat Rev Immunol. 2010; 10: 826-837Crossref PubMed Scopus (2045) Google Scholar,12Rock KL Latz E Ontiveros F Kono H The sterile inflammatory response.Annu Rev Immunol. 2010; 28: 321-342Crossref PubMed Scopus (613) Google Scholar,13Eigenbrod T Park JH Harder J Iwakura Y Núñez G Cutting edge: critical role for mesothelial cells in necrosis-induced inflammation through the recognition of IL-1α released from dying cells.J Immunol. 2008; 181: 8194-8198Crossref PubMed Scopus (187) Google Scholar,14Soehnlein O Lindbom L Phagocyte partnership during the onset and resolution of inflammation.Nat Rev Immunol. 2010; 10: 427-439Crossref PubMed Scopus (720) Google Scholar The events include (a) both passive and active release from injured cells or macrophages of intracellular cytokines such as interleukin (IL)-1α that stimulate parenchymal cells to produce chemokines that recruit neutrophils; (b) classical activation of resident macrophages by damage-associated molecular patterns (DAMPs) or pathogen-associated molecular patterns (PAMPs) that interact with pattern recognition receptors to produce high levels of proinflammatory cytokines as well as reactive nitrogen and reactive oxygen species that induce the acute phase response of inflammation. The literature on the anti-inflammatory effects of MSCs is continuing to expand at a rapid rate with over 500 entries in PubMed under “MSCs and inflammation.” We are unable to review all the entries in detail, and therefore we elected to focus here on several examples in which the anti-inflammatory effects of MSCs appear to be best explained at the cellular and molecular levels. The examples deal with inflammation of tissues as a discrete process and not as a component of adaptive immunity, a topic that has been covered in other recent reviews.15Uccelli A Prockop DJ Why should mesenchymal stem cells (MSCs) cure autoimmune diseases?.Curr Opin Immunol. 2010; 22: 768-774Crossref PubMed Scopus (121) Google Scholar,16Tolar J Villeneuve P Keating A Mesenchymal stromal cells for graft-versus-host disease.Hum Gene Ther. 2011; 22: 257-262Crossref PubMed Scopus (48) Google Scholar,17English K Mahon BP Allogeneic mesenchymal stem cells: agents of immune modulation.J Cell Biochem. 2011; 112: 1963-1968Crossref PubMed Scopus (111) Google Scholar,18Singer NG Caplan AI Mesenchymal stem cells: mechanisms of inflammation.Annu Rev Pathol. 2011; 6: 457-478Crossref PubMed Scopus (641) Google Scholar One series of experiments were with a model of bleomycin-induced lung injury.19Ortiz LA Dutreil M Fattman C Pandey AC Torres G Go K et al.Interleukin 1 receptor antagonist mediates the antiinflammatory and antifibrotic effect of mesenchymal stem cells during lung injury.Proc Natl Acad Sci USA. 2007; 104: 11002-11007Crossref PubMed Scopus (841) Google Scholar,20Ortiz LA Gambelli F McBride C Gaupp D Baddoo M Kaminski N et al.Mesenchymal stem cell engraftment in lung is enhanced in response to bleomycin exposure and ameliorates its fibrotic effects.Proc Natl Acad Sci USA. 2003; 100: 8407-8411Crossref PubMed Scopus (1200) Google Scholar In the model, intravenous (i.v.) infusion of minimally expanded murine bone marrow-derived MSCs (500,000 cells per mouse) decreased the inflammatory response to bleomycin and prevented the lungs from developing fibrosis.19Ortiz LA Dutreil M Fattman C Pandey AC Torres G Go K et al.Interleukin 1 receptor antagonist mediates the antiinflammatory and antifibrotic effect of mesenchymal stem cells during lung injury.Proc Natl Acad Sci USA. 2007; 104: 11002-11007Crossref PubMed Scopus (841) Google Scholar,20Ortiz LA Gambelli F McBride C Gaupp D Baddoo M Kaminski N et al.Mesenchymal stem cell engraftment in lung is enhanced in response to bleomycin exposure and ameliorates its fibrotic effects.Proc Natl Acad Sci USA. 2003; 100: 8407-8411Crossref PubMed Scopus (1200) Google Scholar The beneficial effects of the MSCs were largely explained by the cells being activated to secrete IL-1 receptor antagonist (IL-1ra). The MSCs were effective only when administered at the same time as the bleomycin and not at later time points. This observation suggests that the action of MSCs in this model was exerted in the initial phases of the injury in which there is extensive apoptosis of macrophages.21Ortiz LA Moroz K Liu JY Hoyle GW Hammond T Hamilton RF et al.Alveolar macrophage apoptosis and TNF-α, but not p53, expression correlate with murine response to bleomycin.Am J Physiol. 1998; 275: L1208-L1218PubMed Google Scholar The observations were consistent with demonstrations that the IL-1 pathway plays a central role in the generation of sterile inflammation,13Eigenbrod T Park JH Harder J Iwakura Y Núñez G Cutting edge: critical role for mesothelial cells in necrosis-induced inflammation through the recognition of IL-1α released from dying cells.J Immunol. 2008; 181: 8194-8198Crossref PubMed Scopus (187) Google Scholar,22Chen CJ Kono H Golenbock D Reed G Akira S Rock KL Identification of a key pathway required for the sterile inflammatory response triggered by dying cells.Nat Med. 2007; 13: 851-856Crossref PubMed Scopus (681) Google Scholar and its effects are similar to the effects of tumor necrosis factor-α (TNF-α) in infectious inflammation.4Chen GY Nuñez G Sterile inflammation: sensing and reacting to damage.Nat Rev Immunol. 2010; 10: 826-837Crossref PubMed Scopus (2045) Google Scholar,12Rock KL Latz E Ontiveros F Kono H The sterile inflammatory response.Annu Rev Immunol. 2010; 28: 321-342Crossref PubMed Scopus (613) Google Scholar,23Medzhitov R Origin and physiological roles of inflammation.Nature. 2008; 454: 428-435Crossref PubMed Scopus (3887) Google Scholar Both human and mouse MSCs from the bone marrow express high levels of IL-1ra,19Ortiz LA Dutreil M Fattman C Pandey AC Torres G Go K et al.Interleukin 1 receptor antagonist mediates the antiinflammatory and antifibrotic effect of mesenchymal stem cells during lung injury.Proc Natl Acad Sci USA. 2007; 104: 11002-11007Crossref PubMed Scopus (841) Google Scholar and experiments in culture demonstrated that IL-1ra secreted from MSCs inhibited the production of TNF-α by IL-1α-activated macrophages (RAW 264.7). However, infusion of MSCs in the mouse model of bleomycin-induced lung injury was more effective than recombinant or virally delivered IL-1ra. The results indicated that one way in which MSCs can modulate the early phases of inflammation is to secrete IL-1ra and thereby blunt the effects of IL-1 and TNF-α in stimulating both sterile and infectious inflammation.23Medzhitov R Origin and physiological roles of inflammation.Nature. 2008; 454: 428-435Crossref PubMed Scopus (3887) Google Scholar An analogous mechanism was provided by the observation24Yagi H Soto-Gutierrez A Navarro-Alvarez N Nahmias Y Goldwasser Y Kitagawa Y et al.Reactive bone marrow stromal cells attenuate systemic inflammation via sTNFR1.Mol Ther. 2010; 18: 1857-1864Abstract Full Text Full Text PDF PubMed Scopus (136) Google Scholar that human MSCs (hMSCs) attenuated systemic inflammation in mice after intraperitoneal (i.p.) injection of lipopolysaccharide by secreting soluble receptor-1 for TNF (sTNFR1), which binds to TNF-α and neutralizes the activity of the cytokine. One of the paradoxical observations with MSCs is that i.v. infusions of MSCs produced beneficial effects in repairing tissues in distal organs such as heart, pancreas, brain, and spinal column even though most i.v. infused MSCs are trapped in the lung.11Prockop DJ Kota DJ Bazhanov N Reger RL Evolving paradigms for repair of tissues by adult stem/progenitor cells (MSCs).J Cell Mol Med. 2010; 14: 2190-2199Crossref PubMed Scopus (216) Google Scholar The paradox was at least in part resolved by experiments with hMSCs were infused i.v. in a mouse model for MI.25Lee RH Pulin AA Seo MJ Kota DJ Ylostalo J Larson BL et al.Intravenous hMSCs improve myocardial infarction in mice because cells embolized in lung are activated to secrete the anti-inflammatory protein TSG-6.Cell Stem Cell. 2009; 5: 54-63Abstract Full Text Full Text PDF PubMed Scopus (1387) Google Scholar The i.v. injection of hMSCs (2 × 106 cells per mouse) significantly reduced the early inflammatory response to permanent ligation of the anterior descending coronary artery and subsequently reduced the size of the myocardial infarcts. Also, significant improvement was observed in the function of the left ventricle as assayed by echocardiography 3 weeks later. However, quantitative assays for human Alu sequences and human mRNA for GAPDH as a measure for live hMSCs indicated that only a small fraction of the infused MSCs were recovered in the heart after injection. Also, the appearance of the hMSCs in the heart was transient: about 1,500 of the 2 × 106 were present at 24 hours, and they disappeared by 48 hours. Most of the injected cells were found trapped in the lungs as microemboli25Lee RH Pulin AA Seo MJ Kota DJ Ylostalo J Larson BL et al.Intravenous hMSCs improve myocardial infarction in mice because cells embolized in lung are activated to secrete the anti-inflammatory protein TSG-6.Cell Stem Cell. 2009; 5: 54-63Abstract Full Text Full Text PDF PubMed Scopus (1387) Google Scholar,26Lee RH Seo MJ Pulin AA Gregory CA Ylostalo J Prockop DJ The CD34-like protein PODXL and α6-integrin (CD49f) identify early progenitor MSCs with increased clonogenicity and migration to infarcted heart in mice.Blood. 2009; 113: 816-826Crossref PubMed Scopus (150) Google Scholar and they disappeared with a half-life of 24 hours. In an attempt to explain the beneficial effects of the MSCs, RNA was extracted from lungs of the mice 10 hours after infusion of the hMSCs and was assayed on human microarrays. After filtering for cross hybridization with mouse RNAs, the data indicated that the hMSCs trapped in the lungs as microemboli were activated to upregulate the expression of over 50 human genes. Among the upregulated genes, the most interesting was the gene for the multipotent anti-inflammatory protein referred to as TNF-α stimulated gene/protein 6 (TSG-6). The hMSCs with an siRNA knockdown of the TSG-6 gene had little or no effect in the MI model. Also, the i.v. administration of recombinant human TSG-6 (rhTSG-6) had about the same beneficial effect as hMSCs. The results were explained by a sequence in which the hMSCs were activated by being trapped as microemboli to secrete TSG-6, and the TSG-6 decreased the early and excessive inflammatory response in the heart that causes destruction of cardiac tissue (Figure 1). In effect, by being activated to secrete TSG-6, the MSCs acted at a distance to reduce injury to the heart. I.v. administration of hMSCs was also shown to act at a distance to reduce inflammation in a model of sterile injury to the cornea in rats. The corneas were injured by brief exposure to alcohol followed by mechanical scrapping of the epithelium and limbus that removed the stem cells found in the limbus. i.v. infused hMSCs (1 × 107 cells per rat) markedly decreased neutrophil infiltration, production of proinflammatory cytokines, and development of the opacity in the cornea.27Roddy GW Oh JY Lee RH Bartosh TJ Ylöstalo JH Coble K et al.Action at a distance: Systemically administered adult stem/progenitor cells (MSCs) reduce inflammatory damage to the cornea without engraftment and primarily by secretion of TSG-6.Stem Cells. 2011; 29: 1572-1579Crossref PubMed Scopus (202) Google Scholar Surprisingly, i.p. infusion of the hMSCs was also effective in suppressing inflammation and preventing the opacity in the cornea. A quantitative assay for human mRNA for GAPDH demonstrated that <10 hMSCs were present in the corneas of rats 1 day and 3 days after i.v. or i.p. administration of 1 × 107 hMSCs. However, the hMSCs with an siRNA knockdown of the TSG-6 gene were not effective. Also, the beneficial effects of hMSCs were largely duplicated by i.v. administration of rhTSG-6. Therefore, the data demonstrated that systemically administered hMSCs reduced inflammatory damage to the cornea without engraftment in the tissue and that the anti-inflammatory effects of the cells were probably explained by their secretion of TSG-6. A related series of experiments demonstrated that direct injection of rhTSG-6 into the anterior chamber of the rat eye also decreased excessive inflammation in injured cornea. The anti-inflammatory effects of the rhTSG-6 were dose-dependent (Figure 2).28Oh JY Roddy GW Choi H Lee RH Ylöstalo JH Rosa Jr, RH et al.Anti-inflammatory protein TSG-6 reduces inflammatory damage to the cornea following chemical and mechanical injury.Proc Natl Acad Sci USA. 2010; 107: 16875-16880Crossref PubMed Scopus (179) Google Scholar The effective suppression of excessive inflammation in the early phase of injury subsequently led to a marked decrease in development of blinding opacity and neovascularization of the cornea at day 21 of injury. These data collectively indicate that MSCs effectively protect the heart or cornea from injury and promote tissue regeneration by modulating acute excessive inflammation primarily by secreting TSG-6. The anti-inflammatory action of MSCs through secretion of TSG-6 was further demonstrated in a model in which peritonitis was induced in mice by injection of zymosan, a glucan prepared from the cell walls of yeast.29Choi H Lee RH Bazhanov N Oh JY Prockop DJ Anti-inflammatory protein TSG-6 secreted by activated MSCs attenuates zymosan-induced mouse peritonitis by decreasing TLR2/NF-?B signaling in resident macrophages.Blood. 2011; 118: 330-338Crossref PubMed Scopus (488) Google Scholar After hMSCs (1.6 × 106 cells per mouse) were infused i.p. 15 minutes after zymosan, there was a significantly decrease in neutrophils and monocytes/macrophages in the peritoneal cavity. As in the previous experiments, hMSCs transduced with the TSG-6 siRNA were not effective, and i.p. infusion of 30 µg rhTSG-6 largely reproduced the anti-inflammatory effects of hMSCs. The anti-inflammatory effects of the hMSCs were explained by their effects on resident macrophages, the sentinel cell for inflammatory responses in most tissues.4Chen GY Nuñez G Sterile inflammation: sensing and reacting to damage.Nat Rev Immunol. 2010; 10: 826-837Crossref PubMed Scopus (2045) Google Scholar,12Rock KL Latz E Ontiveros F Kono H The sterile inflammatory response.Annu Rev Immunol. 2010; 28: 321-342Crossref PubMed Scopus (613) Google Scholar,14Soehnlein O Lindbom L Phagocyte partnership during the onset and resolution of inflammation.Nat Rev Immunol. 2010; 10: 427-439Crossref PubMed Scopus (720) Google Scholar In cultures of murine macrophages (RAW 264.7) that were stimulated with zymosan, both hMSCs and rhTSG-6 decreased the secretion of the proinflammatory cytokines, TNF-α and IL-1α. They also suppressed the activation and translocation of the nuclear factor-κB (NF-κB) complex to the nucleus. As expected, hMSCs had no significant effect after the TSG-6 gene was knocked down with an siRNA. The inhibitory effects of hMSCs and TSG-6 were dependent on the expression of CD44, because they did not suppress NF-ĸB signaling in cells or in transgenic mice that did not express CD44. Zymosan stimulates NF-ĸB signaling through the Toll-like receptor 2 (TLR2). The inhibitory action of TSG-6 was dependent on the interaction of CD44 with TLR2 and not on the downstream of TLR2 signaling, since TSG-6 did not inhibit the TLR2/NF-κB pathway in cells overexpressing two of TLR adaptor proteins (MyD88 and TIRAP) that interact with the cytoplasmic tail of TLR2. The overall effect was that the hMSCs introduced a negative feedback loop into the inflammatory response (Figure 3) in which MSCs and TSG-6 suppressed the initial production of proinflammatory cytokines from zymosan-activated macrophages. They thereby inhibited the amplification of the proinflammatory signals by mesothelial cells that produce high levels of IL-6 and CXCL1 to recruit neutrophils.29Choi H Lee RH Bazhanov N Oh JY Prockop DJ Anti-inflammatory protein TSG-6 secreted by activated MSCs attenuates zymosan-induced mouse peritonitis by decreasing TLR2/NF-?B signaling in resident macrophages.Blood. 2011; 118: 330-338Crossref PubMed Scopus (488) Google Scholar TLRs on resident macrophage play critical roles in initiating inflammation in most tissues.4Chen GY Nuñez G Sterile inflammation: sensing and reacting to damage.Nat Rev Immunol. 2010; 10: 826-837Crossref PubMed Scopus (2045) Google Scholar,14Soehnlein O Lindbom L Phagocyte partnership during the onset and resolution of inflammation.Nat Rev Immunol. 2010; 10: 427-439Crossref PubMed Scopus (720) Google Scholar,30Seong SY Matzinger P Hydrophobicity: an ancient damage-associated molecular pattern that initiates innate immune responses.Nat Rev Immunol. 2004; 4: 469-478Crossref PubMed Scopus (955) Google Scholar,31Bauernfeind FG Horvath G Stutz A Alnemri ES MacDonald K Speert D et al.Cutting edge: NF-κB activating pattern recognition and cytokine receptors license NLRP3 inflammasome activation by regulating NLRP3 expression.J Immunol. 2009; 183: 787-791Crossref PubMed Scopus (1862) Google Scholar The negative feedback loop introduced by MSCs and TSG-6 on the TLR2/NF-κB pathway in macrophages may therefore largely account for the beneficial effects of MSCs in other disease models in which excessive inflammatory responses contribute to tissue damage. A different explanation for the anti-inflammatory effects of MSCs was demonstrated in a mouse model of sepsis produced by cecal ligation and puncture.32Németh K Leelahavanichkul A Yuen PS Mayer B Parmelee A Doi K et al.Bone marrow stromal cells attenuate sepsis via prostaglandin E(2)-dependent reprogramming of host macrophages to increase their interleukin-10 production.Nat Med. 2009; 15: 42-49Crossref PubMed Scopus (1807) Google Scholar Németh et al. found that there was a significant improvement in the survival of mice that received 1 × 106 mouse MSCs (mMSCs) i.v. at the time of surgery, 24 hours before or 1 hour after surgery. Also, the serum levels of TNF-α and IL-6, proinflammatory cytokines that have a central role in sepsis,33Ulloa L Tracey KJ The “cytokine profile”: a code for sepsis.Trends Mol Med. 2005; 11: 56-63Abstract Full Text Full Text PDF PubMed Scopus (356) Google Scholar were significantly reduced by administration of the mMSCs. After i.v. infusion, most of the mMSCs were found in the lungs, and they disappeared over time but few were visible 24 hours after injection. Interestingly, the serum level of IL-10, an anti-inflammatory cytokine secreted by macrophages, was elevated at 6 and 12 hours in mice receiving MSCs. Either depletion of macrophages or administration of blocking antibodies to IL-10 eliminated beneficial effects of MSCs in mice with sepsis. MSCs from IL-10−/− mice were still effective in improving the survival of mice with sepsis. Thus, the data suggested that MSCs were not the source of IL-10 but they ameliorated sepsis by inducing IL-10 production in host macrophages. The MSCs apparently induced the production of IL-10 in the macrophages by secreting nitric oxide, but some of the data suggested that the macrophages also produced nitric oxide. A series of in vivo and in vitro experiments demonstrated that TLR4 and TNFR-1-mediated activation of NF-κB in the mMSCs upregulated expression of cyclooxygenase-2 and thereby increased secretion of prostaglandin E2 (PGE2). PGE2 in turn bound to EP2 and EP4 receptors on macrophages and changed macrophages to the phenotype that secretes IL-10. The IL-10 produced by host macrophages reduced inflammation in mice with sepsis (Figure 4). IL-10 is an essential component of a negative feedback loop in inflammation, because it typically inhibits the response that initiated its own production and acts on macrophages and other cells that produce inflammatory mediators.34Medzhitov R Inflammation 2010: new adventures of an old flame.Cell. 2010; 140: 771-776Abstract Full Text Full Text PDF PubMed Scopus (1021) Google Scholar The observations by Nemeth et al.32Németh K Leelahavanichkul A Yuen PS Mayer B Parmelee A Doi K et al.Bone marrow stromal cells attenuate sepsis via prostaglandin E(2)-dependent reprogramming of host macrophages to increase their interleukin-10 production.Nat Med. 2009; 15: 42-49Crossref PubMed Scopus (1807) Google Scholar suggested that MSCs can create another negative feedback loop of inflammation, one that apparently does not involve TSG-6. One caution about the results32Németh K Leelahavanichkul A Yuen PS Mayer B Parmelee A Doi K et al.Bone marrow stromal cells attenuate sepsis via prostaglandin E(2)-dependent reprogramming of host macrophages to increase their interleukin-10 production.Nat Med. 2009; 15: 42-49Crossref PubMed Scopus (1807) Google Scholar was expressed in a subsequent report describing similar experiments with cecal ligation and puncture in mice. Mei et al.35Mei SH Haitsma JJ Dos Santos CC Deng Y Lai PF Slutsky AS et al.Mesenchymal stem cells reduce inflammation while enhancing bacterial clearance and improving survival in sepsis.Am J Respir Crit Care Med. 2010; 182: 1047-1057Crossref PubMed Scopus (520) Google Scholar observed that the mMSCs had beneficial effects but their data indicated a decrease instead of an increase32Németh K Leelahavanichkul A Yuen PS Mayer B Parmelee A Doi K et al.Bone marrow stromal cells attenuate sepsis via prostaglandin E(2)-dependent reprogramming of host macrophages to increase their interleukin-10 production.Nat Med. 2009; 15: 42-49Crossref PubMed Scopus (1807) Google Scholar in serum levels of IL-10 that were assayed 24 hours after i.v. infusion of mouse MSCs. There are several possible explanations for the discrepancy, including differences in when the MSCs were infused, in when the serum was assayed, and in the dose of cells administered. Also, Mei et al. used mMSCs that were extensively characterized and obtained from an NIH-sponsored core facility (http://medicine.tamhsc.edu/irm/msc-distribution.html). Therefore, they minimized the danger of using mMSCs that are easily transformed by overexpansion in culture.11Prockop DJ Kota DJ Bazhanov N Reger RL Evolving paradigms for repair of tissues by adult stem/progenitor cells (MSCs).J Cell Mol Med. 2010; 14: 2190-2199Crossref PubMed Scopus (216) Google Scholar,36Prockop DJ Brenner M Fibbe WE Horwitz E Le Blanc K Phinney DG et al.Defining the risks of mesenchymal stromal cell therapy.Cytotherapy. 2010; 12: 576-578Abstract Full Text Full Text PDF PubMed Scopus (258) Google Scholar The suggestion by Nemeth et al.32Németh K Leelahavanichkul A Yuen PS Mayer B Parmelee A Doi K et al.Bone marrow stromal cells attenuate sepsis via prostaglandin E(2)-dependent reprogramming of host macrophages to increase their interleukin-10 production.Nat Med. 2009; 15: 42-49Crossref PubMed Scopus (1807) Google Scholar that MSCs can reprogram macrophages from a proinflammatory M1 phenotype to the alternatively activated or anti-inflammatory M2 phenotype was supported by several other reports. Kim et al.37Kim J Hematti P Mesenchymal stem cell-educated macrophages: a novel type of alternatively activated macrophages.Exp Hematol. 2009; 37: 1445-1453Abstract Full Text Full Text PDF PubMed Scopus (604) Google Scholar found that human macrophages cocultured with human bone marrow-derived MSCs expressed high levels of a marker of alternatively activated M2 macrophages (CD206, a mannose receptor), high levels of IL-10 and IL-6, and low levels of IL-12 and TNF-α. They had increased phagocytic activity. In parallel observations with mouse MSCs, Maggini et al.38Maggini J Mirkin G Bognanni I Holmberg J Piazzón IM Nepomnaschy I et al.Mouse bone marrow-derived mesenchymal stromal cells turn activated macrophages into a regulatory-like profile.PLoS ONE. 2010; 5: e9252Crossref PubMed Scopus (449) Google Scholar also found that mouse bone marrow-derived MSCs switched macrophages to a regulatory phenotype characterized by decreased expression of inflammatory cytokines, increased phagocytosis of apoptotic cells, and increased susceptibility to infection by intracellular pathogens. The effects were apparently mediated by secretion of PGE2 by the MSCs since acetylsalicylic acid, a cyclooxygenase inhibitor, impaired the ability of MSCs to change the phenotype of the macrophages. In similar experiments with human gingiva-derived MSCs, Zhang et al.39Zhang QZ Su WR Shi SH Wilder-Smith P Xiang AP Wong A et al.Human gingiva-derived mesenchymal stem cells elicit polarization of m2 macrophages and enhance cutaneous wound healing.Stem Cells. 2010; 28: 1856-1868Crossref PubMed Scopus (433) Google Scholar also observed that the MSCs or conditioned medium from the MSCs converted macrophages to the M2 phenotype, and apparently because of the conversion, they enhanced wound repair in vivo. In addition, they found that the MSCs suppressed TNF-α secretion by macrophages in a manner that correlated with impaired activation of NF-ĸB p50. Therefore, there is a large body of evidence that MSCs suppress inflammation and enhance tissue repair by modulating the phenotype of macrophages. The observations that many of the anti-inflammatory effects of MSCs can be reproduced by soluble factors the cells produce raise an obvious question: can therapies with the factors replace therapies with MSCs? Several of the factors are not attractive candidates. For example, therapy with recombinant IL-1ra has been introduced into clinical trials. It appears to have limited applications because improvements were seen in a small number of patients with gout,40So A De Smedt T Revaz S Tschopp J A pilot study of IL-1 inhibition by anakinra in acute gout.Arthritis Res Ther. 2007; 9: R28Crossref PubMed Scopus (616) Google Scholar but there was no benefit in patients with osteoarthritis and rheumatoid arthritis.41Gabay C Lamacchia C Palmer G IL-1 pathways in inflammation and human diseases.Nat Rev Rheumatol. 2010; 6: 232-241Crossref PubMed Scopus (559) Google Scholar Other factors produced by MSCs, such as nitric oxide, indoleamine dioxygenase, or PGE2 are not promising candidates because they have short half-lives or they have adverse effects when administered systemically. However, there appear to be adequate reasons for testing the protein TSG-6 for therapeutic uses. The protein was previously shown to have multiple anti-inflammatory effects in addition to its modulation of NF-ĸB signaling in macrophages29Choi H Lee RH Bazhanov N Oh JY Prockop DJ Anti-inflammatory protein TSG-6 secreted by activated MSCs attenuates zymosan-induced mouse peritonitis by decreasing TLR2/NF-?B signaling in resident macrophages.Blood. 2011; 118: 330-338Crossref PubMed Scopus (488) Google Scholar without any apparent toxic effects, even in transgenic mice overexpressing the gene.42Wisniewski HG Vilcek J Cytokine-induced gene expression at the crossroads of innate immunity, inflammation and fertility: TSG-6 and PTX3/TSG-14.Cytokine Growth Factor Rev. 2004; 15: 129-146Abstract Full Text Full Text PDF PubMed Scopus (123) Google Scholar,43Milner CM Higman VA Day AJ TSG-6: a pluripotent inflammatory mediator?.Biochem Soc Trans. 2006; 34: 446-450Crossref PubMed Scopus (183) Google Scholar Further examination of the beneficial effects of MSCs in disease models may identify additional factors that can be used therapeutically. Among the factors of therapeutic interest is stanniocalcin-1 that is secreted by MSCs in response to signals from apoptotic cells44Block GJ Ohkouchi S Fung F Frenkel J Gregory C Pochampally R et al.Multipotent stromal cells are activated to reduce apoptosis in part by upregulation and secretion of stanniocalcin-1.Stem Cells. 2009; 27: 670-681Crossref PubMed Scopus (0) Google Scholar and that reduces reactive oxygen species by upregulating the expression of uncoupling protein-2 of mitochondria.45Wang Y Huang L Abdelrahim M Cai Q Truong A Bick R et al.Stanniocalcin-1 suppresses superoxide generation in macrophages through induction of mitochondrial UCP2.J Leukoc Biol. 2009; 86: 981-988Crossref PubMed Scopus (76) Google Scholar Since low levels of reactive oxygen species are proinflammatory and high levels are proapoptotic, stanniocalcin-1 may be both anti-inflammatory and antiapoptotic. The role of MSCs as guardians against excessive inflammation explains many of the beneficial effects observed with administration of the cells in animal models for a large number of diseases, including models for lung injury, diabetes, sepsis, MI, sterile injury to the cornea, and stroke. The recent information that has defined the anti-inflammatory factors produced by the cells (summarized in Figure 5) opens the possibility of using one or more of the factors to develop therapies that may be safer, and more widely applicable than therapies with the cells themselves. However, MSCs modulate their anti-inflammatory effects in multiple ways that appear to be responsive to the different microenvironments created by different tissue injuries. Therefore, MSCs may be the therapy of choice for some diseases." @default.
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