title: Toll-like receptor 2 mediates mesenchymal stem cell-associated myocardial recovery and VEGF production following acute ischemia-reperfusion injury.
abstract: Toll-like receptor 2 (TLR2), a key component of the innate immune system, is linked to inflammation and myocardial dysfunction after ischemia-reperfusion injury (I/R). Treatment of the heart with mesenchymal stem cells (MSCs) is known to improve myocardial recovery after I/R in part by paracrine factors such as VEGF. However, it is unknown whether TLR2 activation on the MSCs affects MSC-mediated myocardial recovery and VEGF production. We hypothesized that the knockout of TLR2 on the MSCs (TLR2KO MSCs) would 1) improve MSC-mediated myocardial recovery and 2) increase myocardial and MSC VEGF release. With the isolated heart perfusion system, Sprague-Dawley rat hearts were subjected to I/R and received one of three intracoronary treatments: vehicle, male wild-type MSCs (MWT MSCs), or TL2KO MSCs. All treatments were performed immediately before ischemia, and heart function was measured continuously. Postreperfusion, heart homogenates were analyzed for myocardial VEGF production. Contrary to our hypothesis, only MWT MSC treatment significantly improved the recovery of left ventricular developed pressure and the maximal positive and negative values of the first derivative of pressure. In addition, VEGF production was greatest in hearts treated with MWT MSCs. To investigate MSC production of VEGF, MSCs were activated with TNF in vitro and the supernatants collected for ELISA. In vitro basal levels of MSC VEGF production were similar. However, with TNF activation, MWT MSCs produced significantly more VEGF, whereas activated TLR2KO MSC production of VEGF was unchanged. Finally, we observed that MWT MSCs proliferated more rapidly than TLR2KO MSCs. These data indicate that TLR2 may be essential to MSC-mediated myocardial recovery and VEGF production.
authors.affiliation: Department of Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors.forename: Aaron M
authors.initials: AM
authors.lastname: Abarbanell
authors.forename: Yue
authors.initials: Y
authors.lastname: Wang
authors.forename: Jeremy L
authors.initials: JL
authors.lastname: Herrmann
authors.forename: Brent R
authors.initials: BR
authors.lastname: Weil
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Poynter
authors.forename: Mariuxi C
authors.initials: MC
authors.lastname: Manukyan
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Meldrum
mesh_terms: D017667:Adipocytes / Q000502:physiology; D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D049109:Cell Proliferation; D006321:Heart / Q000502:physiology*; D066298:In Vitro Techniques; D008565:Membrane Proteins / Q000378:metabolism; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015428:Myocardial Reperfusion Injury / Q000378:metabolism / Q000473:pathology*; D010012:Osteogenesis / Q000502:physiology; D020127:Recovery of Function; D051195:Toll-Like Receptor 2 / Q000235:genetics* / Q000502:physiology*; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis*
chemical_list: D008565:Membrane Proteins; D051195:Toll-Like Receptor 2; D042461:Vascular Endothelial Growth Factor A