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

33 Citations (Scopus)

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

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STAT3 Transcription Factor
Mesenchymal Stromal Cells
Apoptosis
Inflammation
Hepatocyte Growth Factor
Ischemia
Somatomedins
Reperfusion
Interleukin-1
Left Ventricular Function
Cellular Immunity
Caspase 3
Vascular Endothelial Growth Factor A
Interleukin-6
Stem Cells
Tumor Necrosis Factor-alpha
Cell Proliferation
Cytokines
Wounds and Injuries

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

Cite this

Intracoronary mesenchymal stem cells promote postischemic myocardial functional recovery, decrease inflammation, and reduce apoptosis via a signal transducer and activator of transcription 3 mechanism. / Poynter, Jeffrey A.; Herrmann, Jeremy L.; Manukyan, Mariuxi C.; Wang, Yue; Abarbanell, Aaron M.; Weil, Brent R.; Brewster, Benjamin D.; Meldrum, Daniel R.

In: Journal of the American College of Surgeons, Vol. 213, No. 2, 08.2011, p. 253-260.

Research output: Contribution to journalArticle

Poynter, Jeffrey A. ; Herrmann, Jeremy L. ; Manukyan, Mariuxi C. ; Wang, Yue ; Abarbanell, Aaron M. ; Weil, Brent R. ; Brewster, Benjamin D. ; Meldrum, Daniel R. / Intracoronary mesenchymal stem cells promote postischemic myocardial functional recovery, decrease inflammation, and reduce apoptosis via a signal transducer and activator of transcription 3 mechanism. In: Journal of the American College of Surgeons. 2011 ; Vol. 213, No. 2. pp. 253-260.
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AU - Manukyan, Mariuxi C.

AU - Wang, Yue

AU - Abarbanell, Aaron M.

AU - Weil, Brent R.

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AU - Meldrum, Daniel R.

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N2 - 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.

AB - 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.

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