Optimal temporal delivery of bone marrow mesenchymal stem cells in rats with myocardial infarction
ABSTRACT This study was designed to determine the optimal time point for bone marrow mesenchymal stem cell (MSC) transplantation after myocardial infarction (MI).
MSCs from donor rats were labeled with DAPI before transplantation. The animals underwent MI by ligation of left anterior descending coronary artery, and received intramyocardial injection of MSCs at 1h, 1 week and 2 weeks after MI, respectively. Sham-operated and MI control groups received equal volume phosphate buffered saline. Cardiac function, histological analysis and immunoblot for troponin T were performed 4 weeks after cell transplantation.
MSC transplantation attenuated left ventricular chamber dilation, reduced infarct size, and improved cardiac function in rats after MI. The greatest benefit was achieved in rats that received cells 1 week after MI, engrafted MSC survival, angiogenesis and functional cardiomyocytes in the injured hearts were more abundant in these rats than that in other transplantation groups.
The optimal functional benefit of MSC transplantation was observed in 1-week transplantation group. At this time point scar formation has not occurred and the inflammation is reduced, which should facilitate integration of transplanted cells and functional recovery.
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ABSTRACT: The myocardial microenvironment plays a decisive role in the survival, migration and differentiation of stem cells. We studied myocardial micro-environmental changes induced by ultrasound-targeted microbubble destruction (UTMD) and their influence on the transplantation of mesenchymal stem cells (MSCs). Various intensities of ultrasound were applied to the anterior chest in canines with myocardial infarction after intravenous injection of microbubbles. The expression of cytokines and adhesion molecules in the infarcted area of the myocardium was detected after three sessions of UTMD in 1 wk. Real-time quantitative reverse transcription polymerase chain reaction (RTQ-PCR) showed that the expression of vascular cell adhesion molecule-1 (VCAM-1), stromal cell-derived factor-1 (SDF-1) and vascular endothelial growth factor (VEGF) in the 1.5 W/cm(2) and 1 W/cm(2) groups was markedly increased compared with the 0.5 W/cm(2) or the control groups (3.8- to 4.7-fold, p < 0.01), and the expression of interleukin-1β (IL-1β) in the 1.5 W/cm(2) group was increased twofold over the 1.0 W/cm(2) group, whereas the 0.5 W/cm(2) group experienced no significant changes. UTMD at 1.0 W/cm(2) was performed as previously described before mesenchymal stem cell (MSC) transplantation. Myocardial perfusion, angiogenesis and heart function were investigated before and 1 month after MSC transplantation. Coronary angiography and 99mTc-tetrofosmin scintigraphy revealed that myocardial perfusion was markedly improved after UTMD + MSCs treatment (p < 0.05). At echocardiographic analysis, heart function and the wall motion score index were significantly improved by UTMD + MSCs treatment compared with MSCs or UTMD alone and the control. In a canine model of myocardial infarction, therapeutic effects were markedly enhanced by MSC transplantation after the myocardial micro-environmental changes induced by UTMD; therefore, this novel method may be useful as an efficient approach for cellular therapy.Ultrasound in medicine & biology 08/2013; 39(11). DOI:10.1016/j.ultrasmedbio.2013.06.003 · 2.10 Impact Factor
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ABSTRACT: Injury to the superficial digital flexor tendon (SDFT) is common in racing and sport horses and poor tendon regeneration leads to high reinjury rates. Autologous mesenchymal stromal cells (MSCs) are being used clinically to improve tendon regeneration but they have some practical limitations. Embryonic stem cells (ESCs) may overcome these limitations but their fate following injection into the damaged SDFT is unknown. To inject MSCs and ESCs into distinct areas of damage in the SDFT and monitor their survival over a 3 month period. MSCs and ESCs expressing different reporter genes were injected into separate sites of mechanically induced damage in SDFTs. Cell survival and distribution were examined post mortem after 10, 30, 60 and 90 days and host immune responses determined. Neither MSCs nor ESCs produced signs of cell-mediated immune response or tumour formation. ESC survival was high and numbers were maintained at a constant level over 90 days. ESCs were present at all sites of damage. In contrast, MSCs showed <5% survival at 10 days and numbers declined over the course of the experiment. MSCs were detected only at the site into which they were injected. ESCs survived in greater numbers than MSCs in the damaged tendon and did not induce an immune response, or form tumours at the injection sites in the 90 day time period studied. ESCs also demonstrated an ability to migrate to other areas of damage within the same tendon, whereas MSCs did not. ESCs can be used allogeneically, therefore providing a possible 'off the shelf' source of cells for therapeutic use which overcomes the practical limitations of autologous MSCs. Furthermore, MSCs and ESCs have different survival rates and migration patterns in the damaged tendon, suggesting that they may produce different functional effects. This may have clinical relevance to treating tendon injuries in the horse.Equine Veterinary Journal 10/2010; 42(7):636-42. DOI:10.1111/j.2042-3306.2010.00112.x · 2.37 Impact Factor
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ABSTRACT: Bone marrow mesenchymal stem cells (MSCs) have the potential to repair the infarcted myocardium and improve cardiac function. However, this approach is limited by its poor viability after transplantation, and controversy still exists over the mechanism by which MSCs contribute to the tissue repair. The human heme oxygenase-1 (hHO-1) was transfected into cultured MSCs using an adenoviral vector. 1 x 10(6) Ad-hHO-1-transfected MSCs (HO-1-MSCs) or Ad-Null-transfected MSCs (Null-MSCs) or PBS only (PBS group) were injected intramyocardially into rat hearts 1h after myocardial infarction. HO-1-MSCs survived in the infarcted myocardium, and expressed hHO-1 mRNA. The expression of basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF) was significantly enhanced in HO-1-MSCs-treated hearts. At the same time, there were significant reduction of TNF-alpha, IL-1-beta and IL-6 mRNA, and marked increase of IL-10 mRNA in HO-1-MSCs-treated hearts. Moreover, a further downregulation of proapoptotic protein, Bax, and a marked increase in microvessel density were observed in HO-1-MSCs-treated hearts. The infarct size and cardiac performance were also significantly improved in HO-1-MSCs-treated hearts. The combined approach improves MSCs survival and is superior to MSCs injection alone.European journal of cardio-thoracic surgery: official journal of the European Association for Cardio-thoracic Surgery 10/2008; 34(4):850-6. DOI:10.1016/j.ejcts.2008.05.049 · 2.81 Impact Factor