title: TLR4 inhibits mesenchymal stem cell (MSC) STAT3 activation and thereby exerts deleterious effects on MSC-mediated cardioprotection.
abstract: BACKGROUND
  Bone marrow-derived mesenchymal stem cells (MSC) improve myocardial recovery after ischemia/reperfusion (I/R) injury. These effects are mediated in part by the paracrine secretion of angiogenic and tissue growth-promoting factors. Toll-like receptor 4 (TLR4) is expressed by MSC and induces apoptosis and inhibits proliferation in neuronal progenitors as well as many other cell types. It is unknown whether knock-out (KO) of TLR4 will change the paracrine properties of MSC and in turn improve MSC-associated myocardial protection.
  
  
  RESULTS
  This study explored the effect of MSC TLR4 on the secretion of angiogenic factors and chemokines in vitro by using ELISA and cytokine array assays and investigated the role of TLR4 on MSC-mediated myocardial recovery after I/R injury in an isolated rat heart model. We observed that MSC isolated from TLR4 KO mice exhibited a greater degree of cardioprotection in a rat model of myocardial I/R injury. This enhanced protection was associated with increased angiogenic factor production, proliferation and differentiation. TLR4-deficiency was also associated with decreased phosphorylation of PI-3K and AKT, but increased activation of STAT3. siRNA targeting of STAT3 resulted in attenuation of the enhanced cardioprotection of TLR4-deficient MSC.
  
  
  CONCLUSIONS
  This study indicates that TLR4 exerts deleterious effects on MSC-derived cardioprotection following I/R by a STAT3 inhibitory mechanism.
authors.affiliation: Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana, United States of America.
authors.forename: Yue
authors.initials: Y
authors.lastname: Wang
authors.forename: Aaron M
authors.initials: AM
authors.lastname: Abarbanell
authors.forename: Jeremy L
authors.initials: JL
authors.lastname: Herrmann
authors.forename: Brent R
authors.initials: BR
authors.lastname: Weil
authors.forename: Mariuxi C
authors.initials: MC
authors.lastname: Manukyan
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Poynter
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Meldrum
mesh_terms: D000818:Animals; D002316:Cardiotonic Agents / Q000378:metabolism*; D049109:Cell Proliferation; D018960:Hyaluronan Receptors / Q000096:biosynthesis; D008297:Male; D059630:Mesenchymal Stem Cells / Q000166:cytology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009206:Myocardium / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000473:pathology; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000235:genetics* / Q000378:metabolism
chemical_list: D002316:Cardiotonic Agents; D018960:Hyaluronan Receptors; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; C494088:Stat3 protein, rat; C493487:Tlr4 protein, mouse; C495347:Tlr4 protein, rat; D051197:Toll-Like Receptor 4; D019869:Phosphatidylinositol 3-Kinases