Soluble factors from biofilms of wound pathogens modulate human bone marrow-derived stromal cell differentiation, migration, angiogenesis, and cytokine secretion

BMC Microbiology

Joseph C Wenke¹  Christopher R Rathbone¹  Sandra C Becerra¹  Sharanda K Hardy¹  Desiree R Romano¹  Beth E Pollot¹  Carlos J Sanchez Jr¹  Catherine L Ward¹ 

[1]Department of Extremity Trauma and Regenerative Medicine, United States Army Institute of Surgical Research, Fort Sam Houston, San Antonio, TX, USA

关键词: Angiogenesis;    Differentiation;    Wound healing;    Mesenchymal stromal cells;    Biofilm;    Pseudomonas aeruginosa;    Staphylococcus aureus;   

Others  :  1212076
DOI  :  10.1186/s12866-015-0412-x

 received in 2014-09-22, accepted in 2015-03-12,  发布年份 2015

【 摘 要 】

Background

Chronic, non-healing wounds are often characterized by the persistence of bacteria within biofilms - aggregations of cells encased within a self-produced polysaccharide matrix. Biofilm bacteria exhibit unique characteristics from planktonic, or culture-grown, bacterial phenotype, including diminished responses to antimicrobial therapy and persistence against host immune responses. Mesenchymal stromal cells (MSCs) are host cells characterized by their multifunctional ability to undergo differentiation into multiple cell types and modulation of host-immune responses by secreting factors that promote wound healing. While these characteristics make MSCs an attractive therapeutic for wounds, these pro-healing activities may be differentially influenced in the context of an infection (i.e., biofilm related infections) within chronic wounds. Herein, we evaluated the effect of soluble factors derived from biofilms of clinical isolates of Staphylococcus aureus and Pseudomonas aeruginosa on the viability, differentiation, and paracrine activity of human MSCs to evaluate the influence of biofilms on MSC activity in vitro.

Results

Exposure of MSCs to biofilm-conditioned medias of S. aureus and P. aeruginosa resulted in reductions in cell viability, in part due to activation of apoptosis. Similarly, exposure to soluble factors from biofilms was also observed to diminish the migration ability of cells and to hinder multi-lineage differentiation of MSCs. In contrast to these findings, exposure of MSCs to soluble factors from biofilms resulted in significant increases in the release of paracrine factors involved in inflammation and wound healing.

Conclusions

Collectively, these findings demonstrate that factors produced by biofilms can negatively impact the intrinsic properties of MSCs, in particular limiting the migratory and differentiation capacity of MSCs. Consequently, these studies suggest use/application of stem-cell therapies in the context of infection may have a limited therapeutic effect.

【 授权许可】

   
2015 Ward et al.; licensee BioMed Central.

【 图 表 】

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【 参考文献 】

• [1]Tarnuzzer RW, Schultz GS. Biochemical analysis of acute and chronic wound environments. Wound Repair Regen. 1996; 4(3):321-5.
• [2]Fazli M, Bjarnsholt T, Kirketerp-Moller K, Jorgensen B, Andersen AS, Krogfelt KA et al.. Nonrandom distribution of Pseudomonas aeruginosa and Staphylococcus aureus in chronic wounds. J Clin Microbiol. 2009; 47(12):4084-9.
• [3]Gjodsbol K, Christensen JJ, Karlsmark T, Jorgensen B, Klein BM, Krogfelt KA. Multiple bacterial species reside in chronic wounds: a longitudinal study. Int Wound J. 2006; 3(3):225-31.
• [4]James GA, Swogger E, Wolcott R, Pulcini E, Secor P, Sestrich J et al.. Biofilms in chronic wounds. Wound Repair Regen. 2008; 16(1):37-44.
• [5]Scali C, Kunimoto B. An update on chronic wounds and the role of biofilms. J Cutan Med Surg. 2013; 17(6):371-6.
• [6]Palmer MP, Altman DT, Altman GT, Sewecke JJ, Ehrlich GD, Hu FZ et al.. Can we trust intraoperative culture results in nonunions? J Orthop Trauma. 2014; 28(7):384-90.
• [7]Percival SL, Cutting KF. Biofilms: possible strategies for suppression in chronic wounds. Nurs Stand. 2009; 23(32):64. 66, 68 passim
• [8]Dominici M, Le Blanc K, Mueller I, Slaper-Cortenbach I, Marini F, Krause D et al.. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy. 2006; 8(4):315-7.
• [9]Caplan AI, Correa D. The MSC: an injury drugstore. Cell Stem Cell. 2011; 9(1):11-5.
• [10]Jackson L, Jones DR, Scotting P, Sottile V. Adult mesenchymal stem cells: differentiation potential and therapeutic applications. J Postgrad Med. 2007; 53(2):121-7.
• [11]Bleul CC, Fuhlbrigge RC, Casasnovas JM, Aiuti A, Springer TA. A highly efficacious lymphocyte chemoattractant, stromal cell-derived factor 1 (SDF-1). J Exp Med. 1996; 184(3):1101-9.
• [12]Stoicov C, Li H, Liu JH, Houghton J. Mesenchymal Stem Cells Utilize CXCR4-SDF-1 Signaling for Acute, but Not Chronic, Trafficking to Gastric Mucosal Inflammation. Dig Dis Sci. 2013; 58(9):2466-77.
• [13]van den Broek LJ, Kroeze KL, Waaijman T, Breetveld M, Sampat-Sardjoepersad SC, Niessen FB et al.. Differential response of human adipose tissue-derived mesenchymal stem cells, dermal fibroblasts and keratinocytes to burn wound exudates: potential role of skin specific chemokine CCL27. Tissue Eng Part A. 2014; 20(1-2):197-209.
• [14]Coffelt SB, Marini FC, Watson K, Zwezdaryk KJ, Dembinski JL, LaMarca HL et al.. The pro-inflammatory peptide LL-37 promotes ovarian tumor progression through recruitment of multipotent mesenchymal stromal cells. Proc Natl Acad Sci U S A. 2009; 106(10):3806-11.
• [15]Lande R, Gregorio J, Facchinetti V, Chatterjee B, Wang YH, Homey B et al.. Plasmacytoid dendritic cells sense self-DNA coupled with antimicrobial peptide. Nature. 2007; 449(7162):564-9.
• [16]Nijnik A, Hancock RE. The roles of cathelicidin LL-37 in immune defences and novel clinical applications. Curr Opin Hematol. 2009; 16(1):41-7.
• [17]Tomchuck SL, Zwezdaryk KJ, Coffelt SB, Waterman RS, Danka ES, Scandurro AB. Toll-like receptors on human mesenchymal stem cells drive their migration and immunomodulating responses. Stem Cells. 2008; 26(1):99-107.
• [18]Rahyussalim A, Kusnadi Y, Ismail H, Lubis A, Kurniawati T, Merlina M. Effect of Staphylococcus aureus and Staphylococcus epidermidis debris and supernatant on bone marrow stromal cells growth. Acta Med Indones. 2012; 44(4):304-9.
• [19]Ding J, Ghali O, Lencel P, Broux O, Chauveau C, Devedjian JC et al.. TNF-alpha and IL-1beta inhibit RUNX2 and collagen expression but increase alkaline phosphatase activity and mineralization in human mesenchymal stem cells. Life Sci. 2009; 84(15–16):499-504.
• [20]Navarro M, Pu F, Hunt JA. The significance of the host inflammatory response on the therapeutic efficacy of cell therapies utilising human adult stem cells. Exp Cell Res. 2012; 318(4):361-70.
• [21]Fiedler T, Salamon A, Adam S, Herzmann N, Taubenheim J, Peters K. Impact of bacteria and bacterial components on osteogenic and adipogenic differentiation of adipose-derived mesenchymal stem cells. Exp Cell Res. 2013; 319(18):2883-2892.
• [22]Beenken KE, Blevins JS, Smeltzer MS. Mutation of sarA in Staphylococcus aureus limits biofilm formation. Infect Immun. 2003; 71(7):4206-11.
• [23]Sanchez CJ, Mende K, Beckius ML, Akers KS, Romano DR, Wenke JC et al.. Biofilm formation by clinical isolates and the implications in chronic infections. BMC Infect Dis. 2013; 13:47.
• [24]Sanchez CJ, Ward CL, Romano DR, Hurtgen BJ, Hardy SK, Woodbury RL, Trevino AV, Rathbone CR, Wenke JC. Staphylococcus aureus biofilms decrease osteoblast viability, inhibits osteogenic differentiation, and increases bone resorption in vitro. BMC Musculoskelet Disord. 2013; 14:187.
• [25]Secor PR, James GA, Fleckman P, Olerud JE, McInnerney K, Stewart PS. Staphylococcus aureus Biofilm and Planktonic cultures differentially impact gene expression, mapk phosphorylation, and cytokine production in human keratinocytes. BMC Microbiol. 2011; 11:143.
• [26]Mo IF, Yip KH, Chan WK, Law HK, Lau YL, Chan GC. Prolonged exposure to bacterial toxins downregulated expression of toll-like receptors in mesenchymal stromal cell-derived osteoprogenitors. BMC Cell Biol. 2008; 9:52.
• [27]Hentze H, Schwoebel F, Lund S, Keel M, Ertel W, Wendel A et al.. In vivo and in vitro evidence for extracellular caspase activity released from apoptotic cells. Biochem Biophys Res Commun. 2001; 283(5):1111-7.
• [28]Belibasakis GN, Meier A, Guggenheim B, Bostanci N. The RANKL-OPG system is differentially regulated by supragingival and subgingival biofilm supernatants. Cytokine. 2011; 55(1):98-103.
• [29]Annabi B, Lee YT, Turcotte S, Naud E, Desrosiers RR, Champagne M et al.. Hypoxia promotes murine bone-marrow-derived stromal cell migration and tube formation. Stem Cells. 2003; 21(3):337-47.
• [30]Kachgal S, Carrion B, Janson IA, Putnam AJ. Bone marrow stromal cells stimulate an angiogenic program that requires endothelial MT1-MMP. J Cell Physiol. 2012; 227(11):3546-55.
• [31]Tang J, Wang J, Yang J, Kong X, Zheng F, Guo L et al.. Mesenchymal stem cells over-expressing SDF-1 promote angiogenesis and improve heart function in experimental myocardial infarction in rats. Eur J Cardiothorac Surg. 2009; 36(4):644-50.
• [32]Liao W, Xie J, Zhong J, Liu Y, Du L, Zhou B et al.. Therapeutic effect of human umbilical cord multipotent mesenchymal stromal cells in a rat model of stroke. Transplantation. 2009; 87(3):350-9.
• [33]Estrada R, Li N, Sarojini H, An J, Lee MJ, Wang E. Secretome from mesenchymal stem cells induces angiogenesis via Cyr61. J Cell Physiol. 2009; 219(3):563-71.
• [34]Kode JA, Mukherjee S, Joglekar MV, Hardikar AA. Mesenchymal stem cells: immunobiology and role in immunomodulation and tissue regeneration. Cytotherapy. 2009; 11(4):377-91.
• [35]Petrie Aronin CE, Tuan RS. Therapeutic potential of the immunomodulatory activities of adult mesenchymal stem cells. Birth Defects Res C Embryo Today. 2010; 90(1):67-74.
• [36]Waterman RS, Tomchuck SL, Henkle SL, Betancourt AM. A new mesenchymal stem cell (MSC) paradigm: polarization into a pro-inflammatory MSC1 or an Immunosuppressive MSC2 phenotype. PLoS One. 2010; 5(4):e10088.
• [37]Thomson CH. Biofilms: do they affect wound healing? Int Wound J. 2011; 8(1):63-7.
• [38]Black CE, Costerton JW. Current concepts regarding the effect of wound microbial ecology and biofilms on wound healing. Surg Clin North Am. 2010; 90(6):1147-60.
• [39]Schierle CF, De la Garza M, Mustoe TA, Galiano RD. Staphylococcal biofilms impair wound healing by delaying reepithelialization in a murine cutaneous wound model. Wound Repair Regen. 2009; 17(3):354-9.
• [40]Malic S, Hill KE, Playle R, Thomas DW, Williams DW. In vitro interaction of chronic wound bacteria in biofilms. J Wound Care. 2011; 20(12):569. –570, 572, 574–567
• [41]Kirker KR, James GA, Fleckman P, Olerud JE, Stewart PS. Differential effects of planktonic and biofilm MRSA on human fibroblasts. Wound Repair Regen. 2012; 20(2):253-61.
• [42]Secor PR, Jennings LK, James GA, Kirker KR, Pulcini ED, McInnerney K et al.. Phevalin (aureusimine B) production by Staphylococcus aureus biofilm and impacts on human keratinocyte gene expression. PLoS One. 2012; 7(7):e40973.
• [43]Li Y, Liu YH, Li ZJ, Liu MY, Li YG, Jin H et al.. Staphylococcus aureus infection of intestinal epithelial cells induces human umbilical cord-derived mesenchymal stem cell migration. Int Immunopharmacol. 2013; 15(1):176-81.
• [44]Im E, Choi YJ, Kim CH, Fiocchi C, Pothoulakis C, Rhee SH. The angiogenic effect of probiotic Bacillus polyfermenticus on human intestinal microvascular endothelial cells is mediated by IL-8. Am J Physiol Gastrointest Liver Physiol. 2009; 297(5):G999-1008.
• [45]Liotta F, Angeli R, Cosmi L, Fili L, Manuelli C, Frosali F et al.. Toll-like receptors 3 and 4 are expressed by human bone marrow-derived mesenchymal stem cells and can inhibit their T-cell modulatory activity by impairing Notch signaling. Stem Cells. 2008; 26(1):279-89.
• [46]Brandau S, Jakob M, Hemeda H, Bruderek K, Janeschik S, Bootz F et al.. Tissue-resident mesenchymal stem cells attract peripheral blood neutrophils and enhance their inflammatory activity in response to microbial challenge. J Leukoc Biol. 2010; 88(5):1005-15.
• [47]Raicevic G, Najar M, Stamatopoulos B, De Bruyn C, Meuleman N, Bron D et al.. The source of human mesenchymal stromal cells influences their TLR profile as well as their functional properties. Cell Immunol. 2011; 270(2):207-16.
• [48]Mastri M, Shah Z, McLaughlin T, Greene CJ, Baum L, Suzuki G et al.. Activation of Toll-like receptor 3 amplifies mesenchymal stem cell trophic factors and enhances therapeutic potency. Am J Physiol Cell Physiol. 2012; 303(10):C1021-33.
• [49]Bocker W, Docheva D, Prall WC, Egea V, Pappou E, Rossmann O et al.. IKK-2 is required for TNF-alpha-induced invasion and proliferation of human mesenchymal stem cells. J Mol Med (Berl). 2008; 86(10):1183-92.
• [50]Bouffi C, Bony C, Courties G, Jorgensen C, Noel D. IL-6-dependent PGE2 secretion by mesenchymal stem cells inhibits local inflammation in experimental arthritis. PLoS One. 2010; 5(12):e14247.
• [51]van der Poll T, Keogh CV, Guirao X, Buurman WA, Kopf M, Lowry SF. Interleukin-6 gene-deficient mice show impaired defense against pneumococcal pneumonia. J Infect Dis. 1997; 176(2):439-44.
• [52]Luster AD. Chemokines–chemotactic cytokines that mediate inflammation. N Engl J Med. 1998; 338(7):436-45.
• [53]Crisostomo PR, Wang Y, Markel TA, Wang M, Lahm T, Meldrum DR. Human mesenchymal stem cells stimulated by TNF-alpha, LPS, or hypoxia produce growth factors by an NF kappa B- but not JNK-dependent mechanism. Am J Physiol Cell Physiol. 2008; 294(3):C675-82.
• [54]Krasnodembskaya A, Song Y, Fang X, Gupta N, Serikov V, Lee JW et al.. Antibacterial effect of human mesenchymal stem cells is mediated in part from secretion of the antimicrobial peptide LL-37. Stem Cells. 2010; 28(12):2229-38.