Amado, LC, Saliaris, AP, Schuleri, KH, St John, M, Xie, JS, Cattaneo, S et al.. Cardiac repair with intramyocardial injection of allogeneic mesenchymal stem cells after myocardial infarction. Proc Natl Acad Sci USA 102: 11474-11479

Department of Medicine, Cardiology Division, The Johns Hopkins Hospital, Blalock 618, 600 North Wolfe Street, Baltimore, MD 21287, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 09/2005; 102(32):11474-9. DOI: 10.1073/pnas.0504388102
Source: PubMed


Although clinical trials of autologous whole bone marrow for cardiac repair demonstrate promising results, many practical and mechanistic issues regarding this therapy remain highly controversial. Here, we report the results of a randomized study of bone-marrow-derived mesenchymal stem cells, administered to pigs, which offer several new insights regarding cellular cardiomyoplasty. First, cells were safely injected by using a percutaneous-injection catheter 3 d after myocardial infarction. Second, cellular transplantation resulted in long-term engraftment, profound reduction in scar formation, and near-normalization of cardiac function. Third, transplanted cells were pre-prepared from an allogeneic donor and were not rejected, a major practical advance for widespread application of this therapy. Together, these findings demonstrate that the direct injection of cellular grafts into damaged myocardium is safe and effective in the perii-nfarct period. The direct delivery of cells to necrotic myocardium offers a valuable alternative to intracoronary cell injections, and the use of allogeneic mesenchymal stem cells provides a valuable strategy for cardiac regenerative therapy that avoids the need for preparing autologous cells from the recipient.

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Available from: Alan Heldman, Aug 04, 2014
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    • "Recently, an increasing number of studies have been conducted, aiming at regenerating infarcted myocardium by injecting cells into the damaged area [1]–[7]. Direct intramyocardial injection is an appealing technique, as the infarcted area can be targeted with high local cell concentrations in comparison to intracoronary application [8], [9]. Cardiac stem cell transplantation has been investigated in numerous randomized clinical studies [10]–[13]. "
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    ABSTRACT: Background The limited effectiveness of cardiac cell therapy has generated concern regarding its clinical relevance. Experimental studies show that cell retention and engraftment are low after injection into ischemic myocardium, which may restrict therapy effectiveness significantly. Surgical aspects and mechanical loss are suspected to be the main culprits behind this phenomenon. As current techniques of monitoring intramyocardial injections are complex and time-consuming, the aim of the study was to develop a fast and simple model to study cardiac retention and distribution following intramyocardial injections. For this purpose, our main hypothesis was that macroscopic fluorescence imaging could adequately serve as a detection method for intramyocardial injections. Methods and Results A total of 20 mice underwent ligation of the left anterior descending artery (LAD) for myocardial infarction. Fluorescent microspheres with cellular dimensions were used as cell surrogates. Particles (5×105) were injected into the infarcted area of explanted resting hearts (Ex vivo myocardial injetions EVMI, n = 10) and in vivo into beating hearts (In vivo myocardial injections IVMI, n = 10). Microsphere quantification was performed by fluorescence imaging of explanted organs. Measurements were repeated after a reduction to homogenate dilutions. Cardiac microsphere retention was 2.78×105±0.31×105 in the EVMI group. In the IVMI group, cardiac retention of microspheres was significantly lower (0.74×105±0.18×105; p<0.05). Direct fluorescence imaging revealed venous drainage through the coronary sinus, resulting in a microsphere accumulation in the left (0.90×105±0.20×105) and the right (1.07×105±0.17×105) lung. Processing to homogenates involved further particle loss (p<0.05) in both groups. Conclusions We developed a fast and simple direct fluorescence imaging method for biodistribution analysis which enabled the quantification of fluorescent microspheres after intramyocardial delivery using macroscopic fluorescence imaging. This new technique showed massive early particle loss and venous drainage into the right atrium leading to substantial accumulation of graft particles in both lungs.
    PLoS ONE 08/2014; 9(8):e101775. DOI:10.1371/journal.pone.0101775 · 3.23 Impact Factor
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    • "Furthermore, many studies have demonstrated that BMSCs play a critical role in injury healing. BMSC transplantation is also regarded as a useful therapeutic strategy in acute tissue injuries of the lung, heart, liver, and kidney [9] [10] [11] [12]. Of note, in all of these preclinical and clinical studies, the engraftment of BMSCs into damaged tissues via migration to suppress immune responses or enhance tissue repair/regeneration is a crucial process for clinical therapy [13]. "
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    ABSTRACT: The recruitment of bone marrow-derived mesenchymal stem cells (BMSCs) to damaged tissues and sites of inflammation is an essential step for clinical therapy. However, the signals regulating the motility of these cells are still not fully understood. Sphingosine-1-phosphate (S1P), a bioactive sphingolipid metabolite, is known to have a variety of biological effects on various cells. Here, we investigated the roles of S1P and S1P receptors (S1PRs) in migration of human BMSCs. We found that S1P exerted a powerful migratory action on human BMSCs. Moreover, by employing RNA interference technology and pharmacological tools, we demonstrated that S1PR1 and S1PR3 are responsible for S1P-induced migration of human BMSCs. In contrast, S1PR2 mediates the inhibition of migration. Additionally, we explored the downstream signaling pathway of the S1P/S1PRs axis and found that activation of S1PR1 or S1PR3 increased migration of human BMSCs through a G i /extracellular regulated protein kinases 1/2- (ERK1/2-) dependent pathway, whereas activation of S1PR2 decreased migration through the Rho/Rho-associated protein kinase (ROCK) pathway. In conclusion, we reveal that the S1P/S1PRs signaling axis regulates the migration of human BMSCs via a dual-directional mechanism. Thus, selective modulation of S1PR’s activity on human BMSCs may provide an effective approach to immunotherapy or tissue regeneration.
    Mediators of Inflammation 07/2014; 2014(4):565369. DOI:10.1155/2014/565369 · 3.24 Impact Factor
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    • "Mesenchymal stem cells (MSCs) are the most commonly used cells in tissue engineering [2-4] and are found in several organic compartments, including the bone marrow, blood vessels, skin, and fat and muscle tissues [5]. MSCs can differentiate into osteogenic cells [6-8], chondrogenic cells [8,9], adipogenic cells [10] and cardiogenic cells [11] in response to different stimuli. "
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    ABSTRACT: Introduction The optimization of an organic scaffold for specific types of applications and cells is vital to successful tissue engineering. In this study, we investigated the effects of a new fibrin sealant derived from snake venom as a scaffold for mesenchymal stem cells, to demonstrate the ability of cells to affect and detect the biological microenvironment. Methods The characterization of CD34, CD44 and CD90 expression on mesenchymal stem cells was performed by flow cytometry. In vitro growth and cell viability were evaluated by light and electron microscopy. Differentiation into osteogenic, adipogenic and chondrogenic lineages was induced. Results The fibrin sealant did not affect cell adhesion, proliferation or differentiation and allowed the adherence and growth of mesenchymal stem cells on its surface. Hoechst 33342 and propidium iodide staining demonstrated the viability of mesenchymal stem cells in contact with the fibrin sealant and the ability of the biomaterial to maintain cell survival. Conclusions The new fibrin sealant is a three-dimensional scaffolding candidate that is capable of maintaining cell survival without interfering with differentiation, and might also be useful in drug delivery. Fibrin sealant has a low production cost, does not transmit infectious diseases from human blood and has properties of a suitable scaffold for stem cells because it permits the preparation of differentiated scaffolds that are suitable for every need.
    Current Stem Cell Research & Therapy 06/2014; 5(3):78. DOI:10.1186/scrt467 · 2.21 Impact Factor
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