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Delayed Intramyocardial Delivery of Stem Cells after Ischemia Reperfusion Injury in a Murine Model
Published on: September 3, 2020
Intracoronary mesenchymal stem cells promote postischemic myocardial functional recovery, decrease inflammation, and
Jeffrey A Poynter1, Jeremy L Herrmann, Mariuxi C Manukyan
1Department of Surgery, Indiana University School of Medicine, Indianapolis, IN, USA.
Insights
Mesenchymal stem cells (MSCs) protect the heart after ischemia/reperfusion injury. This protection relies on Signal transducer and activator of transcription 3 (STAT3) within MSCs, reducing inflammation and apoptosis.
Area of Science:
- Cardiovascular Research
- Regenerative Medicine
- Stem Cell Biology
Background:
- Signal transducer and activator of transcription 3 (STAT3) plays a role in myocardial apoptosis, proliferation, and immune response post-ischemia/reperfusion (I/R).
- Mesenchymal stem cells (MSCs) produce vascular endothelial growth factor (VEGF) via STAT3 and are known to reduce myocardial injury.
- The specific role of STAT3 within MSCs in mediating cardioprotection after I/R was previously unknown.
Purpose of the Study:
- To investigate whether STAT3 in MSCs is essential for their cardioprotective effects after I/R.
- To test the hypothesis that STAT3 knockout (STAT3KO) in MSCs would impair functional recovery and increase inflammatory and apoptotic signaling in the heart.
Main Methods:
- Male rat hearts underwent 25 minutes of ischemia and 40 minutes of reperfusion using a Langendorff apparatus.
- Hearts received intracoronary infusions of vehicle, wild-type MSCs (WT MSCs), or STAT3KO MSCs before ischemia.
- Cardiac function was monitored, and myocardial homogenates were analyzed for inflammatory cytokines (IL-1, IL-6, TNF-α) and caspase-3 levels. MSCs' production of HGF and IGF-1 was measured in vitro.
Main Results:
- WT MSC treatment resulted in the greatest functional recovery, significantly outperforming STAT3KO MSCs and vehicle treatments.
- STAT3KO MSCs showed no significant functional recovery compared to the vehicle group.
- Hearts treated with WT MSCs had the lowest levels of pro-inflammatory cytokines and caspase-3, indicating reduced inflammation and apoptosis, while STAT3KO MSCs showed intermediate levels.
Conclusions:
- Intracoronary infusion of MSCs significantly improves post-ischemic left ventricular function.
- MSC-mediated cardioprotection is dependent on STAT3 signaling within the stem cells.
- STAT3 in MSCs plays a critical role in reducing pro-apoptotic and pro-inflammatory signaling following myocardial I/R injury.
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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