Intracoronary mesenchymal stem cells promote postischemic myocardial functional recovery, decrease inflammation, and reduce apoptosis via a signal transducer and activator of transcription 3 mechanism

Jeffrey A. Poynter, Jeremy L. Herrmann, Mariuxi C. Manukyan, Yue Wang, Aaron M. Abarbanell, Brent R. Weil, Benjamin D. Brewster, Daniel R. Meldrum

Research output: Contribution to journalArticle

36 Scopus citations

Abstract

Background: Signal transducer and activator of transcription 3 (STAT3) regulates myocardial apoptosis, cellular proliferation, and the immune response after ischemia/reperfusion (I/R). STAT3 is also necessary for the production of vascular endothelial growth factor (VEGF) by mesenchymal stem cells (MSCs), which are known to reduce myocardial injury after I/R. However, it remains unknown whether STAT3 is an important mediator of MSC-based cardioprotection. We hypothesized that knockout of stem cell STAT3 would reduce MSC-derived myocardial functional recovery and increase myocardial inflammatory and apoptotic signaling. Study Design: With a Langendorff apparatus, male rat hearts were subjected to 15 minutes of equilibration and 25 minutes of ischemia, followed by 40 minutes of reperfusion. Immediately before ischemia, hearts received intracoronary infusions of vehicle, wild-type MSCs (WT MSCs) or STAT3 knockout MSCs (STAT3KO MSCs). Heart function was measured continuously. Myocardial homogenates were analyzed for production of interleukin (IL)-1, IL-6, and tumor necrosis factor-α (TNF-α). Additionally, MSC production of hepatocyte growth factor (HGF) and insulin-like growth factor-1 (IGF-1) were measured in vitro. Results: Hearts treated with WT MSCs exhibited the greatest functional recovery, and those treated with STAT3KO MSCs had equivalent recovery to vehicle. The highest proinflammatory cytokine levels were seen in vehicle-treated hearts, and the lowest in the WT MSC group. STAT3KO MSCs produced less IGF-1, but more HGF than WT MSCs. Finally, hearts treated with STAT3KO MSCs or vehicle had significantly higher caspase-3 levels than those treated with WT MSCs. Conclusions: Intracoronary infusions of MSCs improve postischemic left ventricular function and reduce proapoptotic and proinflammatory signaling via a STAT3-dependent mechanism.

Original languageEnglish (US)
Pages (from-to)253-260
Number of pages8
JournalJournal of the American College of Surgeons
Volume213
Issue number2
DOIs
StatePublished - Aug 1 2011

Keywords

  • hepatocyte growth factor
  • HGF
  • I/R
  • IGF
  • IMDM
  • insulin-like growth factor
  • ischemia/reperfusion
  • Iscove's modified Dulbecco's medium
  • knockout
  • KO
  • mesenchymal stem cell
  • MSC
  • signal transducer and activator of transcription 3
  • STAT 3
  • TNF
  • tumor necrosis factor
  • vascular endothelial growth factor
  • VEGF
  • wild-type
  • WT

ASJC Scopus subject areas

  • Surgery

Fingerprint Dive into the research topics of 'Intracoronary mesenchymal stem cells promote postischemic myocardial functional recovery, decrease inflammation, and reduce apoptosis via a signal transducer and activator of transcription 3 mechanism'. Together they form a unique fingerprint.

  • Cite this