Optimal temporal delivery of bone marrow mesenchymal stem cells in rats with myocardial infarction

Department of Cardiology, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, 3 East Qing Chun Road, Hangzhou 310016, China.
European Journal of Cardio-Thoracic Surgery (Impact Factor: 3.3). 04/2007; 31(3):438-43. DOI: 10.1016/j.ejcts.2006.11.057
Source: PubMed


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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    • "The myocardial micro-environment plays a decisive role in the survival, migration and differentiation of stem cells, and may determine the biological effect induced by stem cells (Greco et al. 2008; Takahashi et al. 2006). Most engrafted stem cells are killed in the infracted zone because of the harsh environment, including ischemia/reperfusion injury and inflammatory factors, which may decrease the efficacy of stem cell transplantation (Hu et al. 2007). Therefore, providing a suitable local environment to allow stem cells to survive and differentiate is the focus of many studies. "
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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.
    Full-text · Article · Aug 2013 · Ultrasound in medicine & biology
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    • "As early as 12–24 hours after myocardial infarction, early fibrin-rich granulation tissue begins to invade the infarct site, and forms a loose collection of pre-scar tissue for up to 2 weeks post-infarction [59], [60]. Granulation tissue is richly vascularized in the infarct border zone and has been shown to be a suitable environment for cell implantation therapies [60], [61]. "
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    ABSTRACT: The mammalian heart has little capacity to regenerate, and following injury the myocardium is replaced by non-contractile scar tissue. Consequently, increased wall stress and workload on the remaining myocardium leads to chamber dilation, dysfunction, and heart failure. Cell-based therapy with an autologous, epigenetically reprogrammed, and cardiac-committed progenitor cell source could potentially reverse this process by replacing the damaged myocardium with functional tissue. However, it is unclear whether cardiac progenitor cell-derived cardiomyocytes are capable of attaining levels of structural and functional maturity comparable to that of terminally-fated cardiomyocytes. Here, we first describe the derivation of mouse induced pluripotent stem (iPS) cells, which once differentiated allow for the enrichment of Nkx2-5(+) cardiac progenitors, and the cardiomyocyte-specific expression of the red fluorescent protein. We show that the cardiac progenitors are multipotent and capable of differentiating into endothelial cells, smooth muscle cells and cardiomyocytes. Moreover, cardiac progenitor selection corresponds to cKit(+) cell enrichment, while cardiomyocyte cell-lineage commitment is concomitant with dual expression of either cKit/Flk1 or cKit/Sca-1. We proceed to show that the cardiac progenitor-derived cardiomyocytes are capable of forming electrically and mechanically coupled large-scale 2D cell cultures with mature electrophysiological properties. Finally, we examine the cell progenitors' ability to form electromechanically coherent macroscopic tissues, using a physiologically relevant 3D culture model and demonstrate that following long-term culture the cardiomyocytes align, and form robust electromechanical connections throughout the volume of the biosynthetic tissue construct. We conclude that the iPS cell-derived cardiac progenitors are a robust cell source for tissue engineering applications and a 3D culture platform for pharmacological screening and drug development studies.
    Full-text · Article · Jun 2013 · PLoS ONE
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    • "Despite the wealth of evidence that these cells have immune-modulatory properties, a recent publication demonstrated that allogeneic MSC administration was not completely immune-privileged as compared with syngeneic MSCs [28]. Of note, the optimal time for functional benefit of MSC transplantation after myocardial infarction was one week given that the absence of scar formation and the reduction in inflammation at this time point facilitate integration of transplanted cells, leading to functional recovery [54]. This result is supported by another study, in which MSC transplantation improved cardiac function, reduced the apoptosis of cardiomyocytes, and increased vessel density much better when administered at one week but not within one hour or after two weeks [55]. "
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    ABSTRACT: The therapeutic potential of mesenchymal stem cell (MSC) transplantation for the treatment of ischemic conditions such as coronary artery disease, peripheral arterial disease, and stroke has been explored in animal models and early-phase clinical trials. A substantial database documents the safety profile of MSC administration to humans in a large number of disease states. The mechanism of the therapeutic effect of MSC transplantation in ischemic disease has been postulated to be due to paracrine, immunomodulatory, and differentiation effects. This review provides an overview of the potential role of MSC-based therapy for critical limb ischemia (CLI), the comparison of MSC cellular therapy with angiogenesis gene therapy in CLI, and the proposed mechanism of action of MSC therapy. Preclinical efficacy data in animal models of hindlimb ischemia, current early-phase human trial data, and considerations for future MSC-based therapy in CLI will also be discussed.
    Preview · Article · Jul 2012 · Stem Cell Research & Therapy
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